Comparison of current to past outcomes in congenital diaphragmatic hernia using mri observed-to-expected total fetal lung volume.

BACKGROUND: Fetal Centers use imaging studies to predict congenital diaphragmatic hernia (CDH) prognosis and the need for fetal therapy. Given improving CDH survival, we hypothesized that current fetal imaging severity predictions no longer reflect true outcomes and fail to justify the risks of fetal therapy. METHODS: We analyzed our single-center contemporary data in a left-sided CDH cohort (n = 58) by prognostic criteria determined by MRI observed-to-expected total fetal lung volumes: severe <25%, moderate 25-35%, and mild >35%. We compared contemporary survival to prior studies and the TOTAL trials. RESULTS: Contemporary survival was significantly higher than past studies for all prognostic classifications (mild 100% vs 80-94%, moderate 95% vs 59-75%, severe 79% vs 13-25%; P < 0.01), and to either control or fetal therapy arms of the TOTAL trials. CONCLUSIONS: Current fetal imaging criteria are overly pessimistic and may lead to unwarranted fetal intervention. Fetal therapies remain experimental. Future studies will require updated prognostic criteria.

Applying citizen science to engage families affected by ovarian cancer in developing genetic service outreach strategies.

Citizen science (CS) approaches involving non-professional researchers (citizens) as research collaborators has been used infrequently in health promotion generally and specifically, in cancer prevention. Standardized CS approaches may be especially useful for developing communication interventions to encourage families to consider cancer genetic services. We engaged survivors of ovarian cancer and their close relatives as CS collaborators to collect and help interpret data to inform content for a website, printed invitation materials, and short-message reminders. We applied an implementation quality framework, and posed four research questions regarding the feasibility of CS: recruitment, data collection, data quality and evaluation of the experience. CS members were recruited through three networks: clinical sites, local and national cancer support organizations, and online ovarian cancer patient support groups. The professional research team operationalized theory-aligned CS tasks, five data collection options, question banks/scripts for creating surveys, structured interviews, online training and ongoing support from research coaches. 14 CS members agreed to the 12-week and 20-hour commitment for an honorarium. CS members opted to do both qualitative and quantitative assessments. CS members collected 261 surveys and 39 structured interviews. The largest number of surveys were collected for Task 1 (n = 102) to assess survivors' reactions to different possible options for motivating survivors to visit a study website; 77% of this data were complete (i.e., no missing values). Data collected for tasks 2, 3, 4, and 5 (e.g., assessment of survivors' and relatives' respective communication preferences) ranged from 10 to 58 surveys (80% to 84% completeness). All data were collected within the specified time frame. CSs reported 17 hours of work on average and regarded the experience positively. Our experience suggests that CS engagement is feasible, can yield comprehensive quantitative and qualitative data, and is achievable in a relatively a short timeline.

Barriers to Sonographer Screening for Fetal Heart Defects: A U.S. National Survey.

OBJECTIVE: We surveyed obstetric sonographers, who are at the forefront of the screening process to determine how barriers to prenatal cardiac screening impacted screening abilities. METHODS: We performed a cross-sectional national survey of obstetric sonographers in the United States using a sampling frame from American Registry of Diagnostic Medical Sonography mailing lists. The web survey measured the ability to obtain and interpret fetal heart images. Several cognitive, sociodemographic, and system-level factors were measured, including intention to perform cardiac imaging. Regression and mediation analyses determined factors associated with intention to perform and ability to obtain and interpret cardiac images. Subgroup analyses of sonographers in tertiary versus nontertiary centers were also performed. RESULTS: Survey response rate either due to noncontact or nonresponse was 40%. Of 480 eligible sonographers, ~30% practiced in tertiary settings. Sonographers had lower intention to perform outflow views compared to 4 chambers. Higher self-efficacy and professional expectations predicted higher odds of intention to perform outflow views (OR 2.8, 95% CI 1.9-4.2 and 1.9, 95% CI 1.1-3.0, respectively). Overall accuracy of image interpretation was 65% (±14%). For the overall cohort and nontertiary subgroup, higher intention to perform outflows was associated with increased accuracy in overall image interpretation. For the tertiary subgroup, self-efficacy and feedback were strongly associated with accuracy. CONCLUSIONS: We identified several modifiable (some heretofore unrecognized) targets to improve prenatal cardiac screening. Priorities identified by sonographers that are associated with screening success should guide future interventions.

Consensus-based care recommendations for adults with myotonic dystrophy type 1.

PURPOSE OF REVIEW: Myotonic dystrophy type 1 (DM1) is a severe, progressive genetic disease that affects between 1 in 3,000 and 8,000 individuals globally. No evidence-based guideline exists to inform the care of these patients, and most do not have access to multidisciplinary care centers staffed by experienced professionals, creating a clinical care deficit. RECENT FINDINGS: The Myotonic Dystrophy Foundation (MDF) recruited 66 international clinicians experienced in DM1 patient care to develop consensus-based care recommendations. MDF created a 2-step methodology for the project using elements of the Single Text Procedure and the Nominal Group Technique. The process generated a 4-page Quick Reference Guide and a comprehensive, 55-page document that provides clinical care recommendations for 19 discrete body systems and/or care considerations. SUMMARY: The resulting recommendations are intended to help standardize and elevate care for this patient population and reduce variability in clinical trial and study environments.

Germline but not somatic de novo mutations are common in human congenital diaphragmatic hernia.

OBJECTIVES: Congenital diaphragmatic hernia (CDH) is a developmental defect of the diaphragm that causes high newborn morbidity and mortality. CDH is considered to be a multifactorial disease, with strong evidence implicating genetic factors. Although recent studies suggest the biological role of deleterious germline de novo variants, the effect of gene variants specific to the diaphragm remains unclear, and few single genes have been definitively implicated in human disease. METHODS: We performed genome sequencing on 16 individuals with CDH and their unaffected parents, including 10 diaphragmatic samples. RESULTS: We did not detect damaging somatic mutations in diaphragms, but identified germline heterozygous de novo functional mutations of 14 genes in nine patients. Although the majority of these genes are not known to be associated with CDH, one patient with CDH and cardiac anomalies harbored a frameshift mutation in NR2F2 (aka COUP-TFII), generating a premature truncation of the protein. This patient also carried a missense variant predicted to be damaging in XIRP2 (aka Myomaxin), a transcriptional target of MEF2A. Both NR2F2 and MEF2A map to chromosome 15q26, where recurring de novo deletions and unbalanced translocations have been observed in CDH. CONCLUSIONS: Somatic variants are not common in CDH. To our knowledge, this is the second case of a germline de novo frameshift mutation in NR2F2 in CDH. Since NR2F2 null mice exhibit a diaphragmatic defect, and XIRP2 is implicated in cardiac development, our data suggest the role of these two variants in the etiology of CDH, and possibly cardiac anomalies.

Etiology and clinical presentation of birth defects: population based study.

Objective To assess causation and clinical presentation of major birth defects.Design Population based case cohort.Setting Cases of birth defects in children born 2005-09 to resident women, ascertained through Utah's population based surveillance system. All records underwent clinical re-review.Participants 5504 cases among 270 878 births (prevalence 2.03%), excluding mild isolated conditions (such as muscular ventricular septal defects, distal hypospadias).Main outcome measures The primary outcomes were the proportion of birth defects with a known etiology (chromosomal, genetic, human teratogen, twinning) or unknown etiology, by morphology (isolated, multiple, minors only), and by pathogenesis (sequence, developmental field defect, or known pattern of birth defects).Results Definite cause was assigned in 20.2% (n=1114) of cases: chromosomal or genetic conditions accounted for 94.4% (n=1052), teratogens for 4.1% (n=46, mostly poorly controlled pregestational diabetes), and twinning for 1.4% (n=16, conjoined or acardiac). The 79.8% (n=4390) remaining were classified as unknown etiology; of these 88.2% (n=3874) were isolated birth defects. Family history (similarly affected first degree relative) was documented in 4.8% (n=266). In this cohort, 92.1% (5067/5504) were live born infants (isolated and non-isolated birth defects): 75.3% (4147/5504) were classified as having an isolated birth defect (unknown or known etiology).Conclusions These findings underscore the gaps in our knowledge regarding the causes of birth defects. For the causes that are known, such as smoking or diabetes, assigning causation in individual cases remains challenging. Nevertheless, the ongoing impact of these exposures on fetal development highlights the urgency and benefits of population based preventive interventions. For the causes that are still unknown, better strategies are needed. These can include greater integration of the key elements of etiology, morphology, and pathogenesis into epidemiologic studies; greater collaboration between researchers (such as developmental biologists), clinicians (such as medical geneticists), and epidemiologists; and better ways to objectively measure fetal exposures (beyond maternal self reports) and closer (prenatally) to the critical period of organogenesis.

Clinical presentation and survival in a population-based cohort of infants with gastroschisis in Utah, 1997-2011.

Typically gastroschisis is considered an isolated birth defect; however, other major malformations are reported to occur in 5-35% of cases depending on inclusion criteria. This study evaluated the associated malformations, small for gestational age, and survival among a clinically well-characterized population-based gastroschisis cohort, delivered from 1997-2011. We used data from Utah's statewide population-based surveillance system, which monitors major structural birth defects among all pregnancy outcomes (i.e., live births, stillbirths, pregnancy terminations, and miscarriages). Of the initial 387 gastroschisis cases, we excluded 51 (13.2%) for the following reasons: inadequately described or macerated fetuses, part of a specific malformation complex or sequence (limb-body wall complex, amniotic band sequence, or a severe form of abdominoschisis), leaving a study sample of 336 clinically confirmed cases. Gastroschisis was isolated non-syndromic in 284 cases (84.5%). One case was syndromic (trisomy 16; 0.3%) and the remaining 51 (15.2%) were classified as multiple: one unrelated major malformation (27; 52.9%); two or more unrelated major malformation or one major with multiple minor anomalies or mild malformations (6; 11.8%); ≥ one distinctive minor anomaly or mild malformation (13; 25.5%); amyoplasia (5; 1.5%). Of the liveborn infants, 63.3% were preterm (delivered at <37 weeks of gestation) and 21.8% were small for gestational age (SGA). SGA was more common in males (38.8%) than females (16%) (P = 0.008). Overall first year survival was high (95.6%); however, preterm infants with congenital intestinal atresia had the highest mortality (13.8%). The high proportion of isolated cases (84.5%) in gastroschisis is similar to that observed in many other phenotypes and not unique to gastroschisis. Because one in every six infants with gastroschisis had a major unrelated malformation, additional malformations should be sought in every newborn with gastroschisis. Infant mortality was low overall but still a significant concern in affected preterm infants with associated congenital intestinal atresia.

Risk factors for Dandy-Walker malformation: a population-based assessment.

Dandy-Walker malformation (DWM) is the most common congenital malformation of the cerebellum, but its causes are largely unknown. An increasing number of genes associated with congenital cerebellar malformations have been identified; however, few studies have examined the potential role of non-genetic, potentially modifiable risk factors. From the National Birth Defects Prevention Study, we examined maternal, paternal, and infant characteristics and maternal conditions and periconceptional exposures (from 1 month before to 3 months after conception) among infants with DWM (n = 160) and unaffected controls (n = 10,200), delivered between 1997 and 2009. Odds ratios, crude (cOR) and adjusted (aOR) were computed using logistic regression. Maternal factors associated with DWM included non-Hispanic black race/ethnicity (aOR = 2.0, 95%CI: 1.3-3.2). Among maternal conditions, a history of infertility increased the risk for DWM (all: aOR = 2.4, 95%CI: 1.3-4.6; multiple: aOR = 3.9, 95%CI: 1.7-8.9). The lack of association with many maternal exposures supports the hypothesis of a major contribution of genetic factors to the risk for DWM; however, the observed associations with maternal non-Hispanic black race/ethnicity and maternal history of infertility indicate that further research into factors underlying these characteristics may uncover potentially modifiable risk factors, acting alone or as a component of gene-environment interactions.

Admission to a dedicated cardiac intensive care unit is associated with decreased resource use for infants with prenatally diagnosed congenital heart disease.

Many factors in the delivery and perinatal care of infants with a prenatal diagnosis of congenital heart disease (CHD) have an impact on outcome and costs. This study sought to determine the modifiable factors in perinatal management that have an impact on postnatal resource use for infants with CHD. The medical records of infants with prenatally diagnosed CHD (August 2006-December 2011) who underwent cardiac surgery before discharge were reviewed. The exclusion criteria ruled out prematurity and intervention or transplantation evaluation before surgery. Clinical characteristics, outcomes, and cost data were collected. Multivariate linear regression models were used to determine the impact of perinatal decisions on hospitalization cost and surrogates of resource use after adjustment for demographic and other risk factors. For the 126 patients who met the study criteria, the median hospital stay was 22 days (range 4-122 days), and the median inflation-adjusted total hospital cost was $107,357 (range $9,746-602,320). The initial admission to the neonatal versus the cardiac intensive care unit (NICU vs. CICU) was independently associated with a 19 % longer hospital stay, a 26 % longer ICU stay, and 47 % more mechanical ventilation days after adjustment for Risk Adjustment for Congenital Heart Surgery, version 1 score, gestation age, genetic abnormality, birth weight, mode of delivery, and postsurgical complications. Weekend versus weekday delivery was not associated with hospital cost or length of hospital stay. For term infants with prenatally diagnosed CHD undergoing surgery before discharge, preoperative admission to the NICU (vs. the CICU) resulted in a longer hospital stay and greater intensive care use. Prenatal planning for infants with CHD should consider the initial place of admission as a modifiable factor for potential lowering of resource use.

A family-based paradigm to identify candidate chromosomal regions for isolated congenital diaphragmatic hernia.

Congenital diaphragmatic hernia (CDH) is a developmental defect of the diaphragm that causes high newborn mortality. Isolated or non-syndromic CDH is considered a multifactorial disease, with strong evidence implicating genetic factors. As low heritability has been reported in isolated CDH, family-based genetic methods have yet to identify the genetic factors associated with the defect. Using the Utah Population Database, we identified distantly related patients from several extended families with a high incidence of isolated CDH. Using high-density genotyping, seven patients were analyzed by homozygosity exclusion rare allele mapping (HERAM) and phased haplotype sharing (HapShare), two methods we developed to map shared chromosome regions. Our patient cohort shared three regions not previously associated with CDH, that is, 2q11.2-q12.1, 4p13 and 7q11.2, and two regions previously involved in CDH, that is, 8p23.1 and 15q26.2. The latter regions contain GATA4 and NR2F2, two genes implicated in diaphragm formation in mice. Interestingly, three patients shared the 8p23.1 locus and one of them also harbored the 15q26.2 segment. No coding variants were identified in GATA4 or NR2F2, but a rare shared variant was found in intron 1 of GATA4. This work shows the role of heritability in isolated CDH. Our family-based strategy uncovers new chromosomal regions possibly associated with disease, and suggests that non-coding variants of GATA4 and NR2F2 may contribute to the development of isolated CDH. This approach could speed up the discovery of the genes and regulatory elements causing multifactorial diseases, such as isolated CDH.

Identification of a prenatal profile of Cornelia de Lange syndrome (CdLS): a review of 53 CdLS pregnancies.

Cornelia de Lange Syndrome (CdLS) is a multisystem developmental disorder characterized by growth retardation, cognitive impairment, external and internal structural malformations, and characteristic facial features. Currently, there are no definitive prenatal screening measures that lead to the diagnosis of CdLS. In this study, documented prenatal findings in CdLS syndrome were analyzed towards the development of a prenatal profile predictive of CdLS. We reviewed 53 cases of CdLS (29 previously reported and 24 unreported) in which prenatal observations/findings were available. The review of these cases revealed a pattern of sonographic findings, including obvious associated structural defects, growth restriction, as well as a more subtle, but strikingly characteristic, facial profile, and suggestive of a recognizable prenatal ultrasonographic profile for CdLS. In addition, the maternal serum marker, PAPP-A, may be reduced and fetal nuchal translucency (NT) may be increased in some pregnancies when measured at an appropriate gestational age. In conclusion, CdLS can be prenatally diagnosed or readily ruled out in a family with a known mutation in a CdLS gene. The characteristic ultrasonographic profile may allow for prenatal diagnosis of CdLS in (1) subsequent pregnancies to a couple with a prior child with CdLS in whom a mutation has not been identified or (2) when there are unexplained pregnancy signs of fetal abnormality, such as oligo- or polyhydramnios, a low maternal serum PAPP-A level and/or increased NT, fetal growth retardation, or structural anomalies consistent with CdLS.

Germline mosaicism in Cornelia de Lange syndrome.

Cornelia de Lange syndrome (CdLS) is a genetic disorder associated with delayed growth, intellectual disability, limb reduction defects, and characteristic facial features. Germline mosaicism has been a described mechanism for CdLS when there are several affected offspring of apparently unaffected parents. Presently, the recurrence risk for CdLS has been estimated to be as high as 1.5%; however, this figure may be an underrepresentation. We report on the molecularly defined germline mosaicism cases from a large CdLS database, representing the first large case series on germline mosaicism in CdLS. Of the 12 families, eight have been previously described; however, four have not. No one specific gene mutation, either in the NIPBL or the SMC1A gene, was associated with an increased risk for germline mosaicism. Suspected or confirmed cases of germline mosaicism in our database range from a conservative 3.4% up to 5.4% of our total cohort. In conclusion, the potential reproductive recurrence risk due to germline mosiacism should be addressed in prenatal counseling for all families who have had a previously affected pregnancy or child with CdLS.

Analysis of skeletal dysplasias in the Utah population.

The Utah Birth Defect Network (UBDN) collects population-based data for Utah on births from all resident women. The prevalence of skeletal dysplasias and epidemiologic characteristics/outcomes were evaluated. Cases categorized as a skeletal dysplasia from all live births, stillbirths, and pregnancy terminations (TAB) between 1999 and 2008 were reviewed by three clinical geneticists. After case review, 153 were included for analysis (88% live births, 3% stillborn, 9% TAB), and categorized by groupings defined by molecular, biochemical, and/or radiographic criteria as outlined in the 2010 Nosology and Classification of Genetic Skeletal Disorders. The overall prevalence for skeletal dysplasias was 3.0 per 10,000 births, and 20.0 per 10,000 stillbirths. The most common diagnostic groups were osteogenesis imperfecta (OI; n = 40; 0.79 per 10,000), thanatophoric dysplasia (n = 22; 0.43 per 10,000), achondroplasia (n = 18; 0.35 per 10,000), and cleidocranial dysplasia (n = 6; 0.12 per 10,000). The most common groups based on the 2010 Nosology and Classification of Genetic Skeletal Disorders were the FGFR3 chondrodysplasia group (n = 41; 0.81 per 10,000), the OI/decreased bone density group (n = 40; 0.79 per 10,000), and the type 2 collagen group (n = 10; 0.2 per 10,000). Median age of postnatal diagnosis was 30 days (range 1-2,162). Of those deceased, 88% were prenatally suspected; of those alive 29% prenatally suspected. Median age of death for live born individuals was 1 day (range 1-1,450 days). Previously reported prevalence rates vary, but our data provide a population-based approach not limited to the perinatal/neonatal period. Understanding the range for survival within each group/diagnosis is beneficial for health care providers when counseling families.

Survey of physicians' approach to severe fetal anomalies.

OBJECTIVE: Standards of care regarding obstetric management of life-threatening anomalies are not defined. It is hypothesised that physicians' management of these pregnancies is variable and influenced by demographic factors. DESIGN: A questionnaire was mailed to members of the Society of Maternal-Fetal Medicine with valid US addresses assessing obstetric management of both 'uniformly lethal' (eg, anencephaly, renal agenesis) and 'uniformly severe, commonly lethal' (eg, trisomy 13 and 18) anomalies. Respondents were asked to answer as if not limited by state/institutional restrictions. Fisher's exact or χ(2) tests were used as appropriate and correction made for multiple comparisons in analyses that were not prespecified. RESULTS: The response rate was 36% (732/2038). Nearly 100% of respondents discuss termination for both uniformly and commonly lethal anomalies. In continuing pregnancies, with patient request for obstetric non-intervention 99% of providers would comply for either uniformly or commonly lethal anomalies. The majority 'encourage' such management, but some were non-directive or discouraged this management. In continuing pregnancies, with patient request for full obstetric intervention the majority of respondents was willing to comply for both uniformly (71%) and commonly (82%) lethal anomalies. While most practitioners 'discouraged' full intervention, some were non-directive or encouraged this management. Demographics and severity of anomaly influenced counselling. CONCLUSION: Discrepancies exist regarding the management of life-threatening fetal anomalies. Patients may be offered different options based on practitioner demographics. The majority of physicians comply with patient wishes. Differences were noted when comparing the management of lethal with that of severe commonly lethal anomalies, suggesting that practitioners make a distinction when counselling patients.

Group A streptococcal puerperal sepsis: initial characterization of virulence factors in association with clinical parameters.

Group A beta-hemolytic streptococcus (GAS) is an uncommon but potentially fatal source of postpartum infection. Pathogenesis in invasive GAS infections has been linked to bacterial virulence factors. In this study, we sought to provide an initial description of potential virulence factors in association with puerperal morbidity by virtue of specific M-protein type antigens. Women with confirmed GAS puerperal infection in the Salt Lake City region were prospectively identified over a 6-year interval (1991-1997). From this cohort, GAS isolates were analyzed with respect to M-serotype and presence of genes encoding the Streptococcal Pyogenic Exotoxins A and B (SPE-A and SPE-B). Bacterial isolates from 18 subjects with GAS puerperal infection underwent M-serotyping and PCR-based genotyping for the speA and speB genes. Among these, 8/18 subjects manifest criteria of severe disease. All 18 isolate strains expressed speB; 6/18 isolates expressed speA. Of the M-serotypes, 8/8 severe disease isolates expressed M-types 1 (N=3) or 28 (N=5). Pulse-field gel electrophoresis did not indicate an outbreak strain among similar isolates. We conclude that in this initial characterization, morbidity among women with GAS puerperal infection is associated with M-types 1 and 28, but not speB genotype.

Reliability of fetal middle cerebral artery velocity measurements: a randomized controlled trial of sonographer training.

OBJECTIVE: The purpose of this study was to determine the reliability of fetal middle cerebral artery (MCA) peak systolic velocity (PSV) measurements at a tertiary care center and to evaluate the effect of targeted training for sonographers. METHODS: Six sonographers were randomized to training modules for fetal MCA PSV or amniotic fluid volume (AFV) measurements. Six fetuses of uncomplicated pregnancies were selected for participation. Middle cerebral artery and AFV measurements were obtained before and after a training module. The intraobserver and interobserver variability (reliability) was calculated with intraclass correlation coefficients and was compared between groups. RESULTS: Administration of the MCA training module increased the number of technically adequate MCA images obtained (odds ratio, 3.95; 95% confidence interval, 1.07-14.65). The intraobserver and inter-observer variability for MCA measurements was significantly reduced after the targeted training module (P = .05). CONCLUSIONS: The reliability of fetal MCA PSV measurements improved after a targeted training program.

Clinical considerations in gastroschisis: incremental advances against a congenital anomaly with severe secondary effects.

Gastroschisis is one of the most challenging congenital anomalies that physicians treat in the first 2 months of life. Over the last 40 years, tremendous progress has been made in the management of this defect. Survival has increased significantly during this period as well. However, gastroschisis still presents the clinician with a unique set of challenges as a result of secondary effects on intestinal development. These challenges or clinical considerations are discussed in this review including a history of the management of the defect, prenatal counseling, prenatal intervention, postnatal and surgical management, complications and long-term outcomes.

Unilateral short femur--what does this mean? Report of 3 cases.

OBJECTIVES: This study aims to: (1) characterize the prenatal diagnosis of short femur; (2) describe typical findings of proximal focal femoral deficiency; and (3) review the most common differential diagnoses for short femur(s). METHODS: We present 3 examples of prenatally diagnosed proximal focal femoral deficiency and briefly reviewed the differential diagnosis of short femur(s) in utero and associations such as ethnic variation, trisomy 21, and diabetic embryopathy. RESULTS: Multiple cases are presented in which a short femur (unilateral or bilateral) is the dominant finding on prenatal ultrasound. The fetuses were extensively examined for other skeletal anomalies, and global skeletal dysplasias are excluded from the differential diagnosis. Prenatal imaging findings are correlated with postnatal history and imaging. CONCLUSION: Prenatal sonography is now widely used as a screening tool, and at times, subtle findings such as an isolated short femur can be seen without other significant anatomic abnormalities. Counseling for the parents can be difficult without some knowledge of the range of associations seen with short femur(s). Proximal focal femoral dysplasia should be considered in the differential diagnosis when a short femur is discovered.

Autosomal recessive hypophosphatasia manifesting in utero with long bone deformity but showing spontaneous postnatal improvement.

CONTEXT: Hypophosphatasia (HPP) is a heritable metabolic disorder of the skeleton that includes variable expressivity conditioned by gene dosage effect and the variety of mutations in the tissue nonspecific alkaline phosphatase (TNSALP) gene. Patient age when skeletal problems first manifest generally predicts the clinical course, with perinatal HPP causing bone disease in utero with postnatal lethality. OBJECTIVE: Our objective was to identify TNSALP mutations and characterize the inheritance pattern of a family with clinically variable HPP with one child manifesting in utero with long bone deformity but showing spontaneous prenatal and postnatal improvement. DESIGN: TNSALP enzyme and substrate analysis and TNSALP mutation analysis were performed on all family members. PATIENTS: A boy with HPP showing long bone deformity that spontaneously improved in utero and after birth is described. His older brother has the childhood form of HPP without findings until after infancy. His parents and twin sister are clinically unaffected. RESULTS: Both boys are compound heterozygotes for the same missense mutations in TNSALP, documenting autosomal recessive inheritance for their HPP. The parents each carry one defective allele. CONCLUSIONS: The patient is an autosomal recessive case of HPP with prenatal long bone deformity but with spontaneous prenatal and postnatal improvement. Thus, prenatal detection by sonography of bowing of long bones from HPP, even with autosomal recessive inheritance, does not necessarily predict lethality but can represent variable expressivity or the effects of modifiers on the TNSALP defect(s).