Expanding the phenotype, genotype and biochemical knowledge of ALG3-CDG.

Congenital disorders of glycosylation (CDGs) are a continuously expanding group of monogenic disorders of glycoprotein and glycolipid biosynthesis that cause multisystem diseases. Individuals with ALG3-CDG frequently exhibit severe neurological involvement (epilepsy, microcephaly, and hypotonia), ocular anomalies, dysmorphic features, skeletal anomalies, and feeding difficulties. We present 10 unreported individuals diagnosed with ALG3-CDG based on molecular and biochemical testing with 11 novel variants in ALG3, bringing the total to 40 reported individuals. In addition to the typical multisystem disease seen in ALG3-CDG, we expand the symptomatology of ALG3-CDG to now include endocrine abnormalities, neural tube defects, mild aortic root dilatation, immunodeficiency, and renal anomalies. N-glycan analyses of these individuals showed combined deficiencies of hybrid glycans and glycan extension beyond Man5 GlcNAc2 consistent with their truncated lipid-linked precursor oligosaccharides. This spectrum of N-glycan changes is unique to ALG3-CDG. These expanded features of ALG3-CDG facilitate diagnosis and suggest that optimal management should include baseline endocrine, renal, cardiac, and immunological evaluation at the time of diagnosis and with ongoing monitoring.

Expanding the spectrum of CEP55-associated disease to viable phenotypes.

Homozygosity for nonsense variants in CEP55 has been associated with a lethal condition characterized by multinucleated neurons, anhydramnios, renal dysplasia, cerebellar hypoplasia, and hydranencephaly (MARCH syndrome) also known as Meckel-like syndrome. Missense variants in CEP55 have not previously been reported in association with disease. Here we describe seven living individuals from five families with biallelic CEP55 variants. Four unrelated individuals with microcephaly, speech delays, and bilateral toe syndactyly all have a common CEP55 variant c.70G>A p.(Glu24Lys) in trans with nonsense variants. Three siblings are homozygous for a consensus splice site variant near the end of the gene. These affected girls all have severely delayed development, microcephaly, and varying degrees of lissencephaly/pachygyria. Here we compare our seven patients with three previously reported families with a prenatal lethal phenotype (MARCH syndrome/Meckel-like syndrome) due to homozygous CEP55 nonsense variants. Our series suggests that individuals with compound heterozygosity for nonsense and missense variants in CEP55 have a different viable phenotype. We show that homozygosity for a splice variant near the end of the CEP55 gene is also compatible with life.

Recurrent De Novo Mutations Affecting Residue Arg138 of Pyrroline-5-Carboxylate Synthase Cause a Progeroid Form of Autosomal-Dominant Cutis Laxa.

Progeroid disorders overlapping with De Barsy syndrome (DBS) are collectively denoted as autosomal-recessive cutis laxa type 3 (ARCL3). They are caused by biallelic mutations in PYCR1 or ALDH18A1, encoding pyrroline-5-carboxylate reductase 1 and pyrroline-5-carboxylate synthase (P5CS), respectively, which both operate in the mitochondrial proline cycle. We report here on eight unrelated individuals born to non-consanguineous families clinically diagnosed with DBS or wrinkly skin syndrome. We found three heterozygous mutations in ALDH18A1 leading to amino acid substitutions of the same highly conserved residue, Arg138 in P5CS. A de novo origin was confirmed in all six probands for whom parental DNA was available. Using fibroblasts from affected individuals and heterologous overexpression, we found that the P5CS-p.Arg138Trp protein was stable and able to interact with wild-type P5CS but showed an altered sub-mitochondrial distribution. A reduced size upon native gel electrophoresis indicated an alteration of the structure or composition of P5CS mutant complex. Furthermore, we found that the mutant cells had a reduced P5CS enzymatic activity leading to a delayed proline accumulation. In summary, recurrent de novo mutations, affecting the highly conserved residue Arg138 of P5CS, cause an autosomal-dominant form of cutis laxa with progeroid features. Our data provide insights into the etiology of cutis laxa diseases and will have immediate impact on diagnostics and genetic counseling.

Neonatal Hospital Course and Outcomes of Live-born Infants with Trisomy 18 at Two Tertiary Care Centers in the United States.

Objectives Trisomy 18 is presumed to be a lethal chromosomal abnormality; medical management of infants with this aneuploidy is controversial. Our objective was to describe our approach and experience with trisomy 18 infants. Study Design We reviewed the initial hospital course, management, and factors predicting discharge from the hospital from two large tertiary care neonatal intensive care units in the southern United States over 26 years. Results Of the 29 infants with trisomy 18, 21 (72%) died in the hospital and 8 (28%) were discharged home. 19 (66%) infants received mechanical ventilation and 10 (34%) received inotropic medications. Eight infants had critical congenital heart defects; only one survived to discharge. Three infants underwent major surgeries; one cardiac surgery, one tracheoesophageal fistula repair, and one myelomeningocele repair. Median length of hospital stay was 14 days (range, 0-78) for all the infants and 31 days (range, 18-66) for those that were discharged home. Factors associated with discharge from the hospital were female sex, higher gestational age, and absence of critical congenital heart defects. Median survival time was 13 days and was significantly longer for females compared with males. Our 1-month and 1-year survival rates were 31% and 3.9% respectively. Conclusion A significant proportion of infants with trisomy 18 were discharged home. These data are helpful in counseling parents of infants with trisomy 18.

High Incidence of Noonan Syndrome Features Including Short Stature and Pulmonic Stenosis in Patients carrying NF1 Missense Mutations Affecting p.Arg1809: Genotype-Phenotype Correlation.

Neurofibromatosis type 1 (NF1) is one of the most frequent genetic disorders, affecting 1:3,000 worldwide. Identification of genotype-phenotype correlations is challenging because of the wide range clinical variability, the progressive nature of the disorder, and extreme diversity of the mutational spectrum. We report 136 individuals with a distinct phenotype carrying one of five different NF1 missense mutations affecting p.Arg1809. Patients presented with multiple café-au-lait macules (CALM) with or without freckling and Lisch nodules, but no externally visible plexiform neurofibromas or clear cutaneous neurofibromas were found. About 25% of the individuals had Noonan-like features. Pulmonic stenosis and short stature were significantly more prevalent compared with classic cohorts (P < 0.0001). Developmental delays and/or learning disabilities were reported in over 50% of patients. Melanocytes cultured from a CALM in a segmental NF1-patient showed two different somatic NF1 mutations, p.Arg1809Cys and a multi-exon deletion, providing genetic evidence that p.Arg1809Cys is a loss-of-function mutation in the melanocytes and causes a pigmentary phenotype. Constitutional missense mutations at p.Arg1809 affect 1.23% of unrelated NF1 probands in the UAB cohort, therefore this specific NF1 genotype-phenotype correlation will affect counseling and management of a significant number of patients.

Trigeminal nerve agenesis with absence of foramina rotunda in Gómez-López-Hernández syndrome.

Gómez-López-Hernández syndrome (GLHS) is a clinical condition traditionally characterized by rhombencephalosynapsis (RS), parieto-occipital alopecia, and trigeminal anesthesia. It is a neurocutaneous disorder with no known etiology. The underlying cause of the trigeminal anesthesia in GLHS has not been examined or reported; it has merely been identified on clinical grounds. In this report, a 10-month-old white female born at 37 weeks gestational age with GLHS underwent a contrast-enhanced CT for the evaluation of craniofacial dysmorphic features. Thin-section bone algorithm images showed absence of bilateral foramina rotunda and trigeminal nerve fibers. The maxillary branch of the trigeminal nerve passes through the foramen rotundum and carries sensory information from the face. This case is unique because trigeminal nerve absence has not been suggested as a possible etiology for trigeminal anesthesia associated with GLHS. It is not known how many cases of GLHS have agenesis of the trigeminal nerve; however, a review of the literature suggests that this patient is the first. The triad of RS, alopecia, and trigeminal anesthesia is specific to GLHS; therefore, early identification of trigeminal nerve agenesis in patients with RS could expedite diagnosis of GLHS, particularly given that the clinical diagnosis of trigeminal anesthesia in neonates is a challenging one. Diagnosing alopecia in newborns is likewise challenging. Early diagnosis could allow for early intervention, especially for ophthalmic complications, which are known to have significant long-term effects. This case illustrates the benefits of CT imaging in the detection of trigeminal nerve and foramina rotunda abnormalities in neonates with suspected GLHS.

Phenocopy of warfarin syndrome in an infant born to a mother with sickle cell anemia and severe transfusional iron overload.

Neonatal chondrodysplasia punctata (CDP) is characterized by epiphyseal stippling and midfacial hypoplasia. CDP is usually inherited, but can be acquired because of maternal vitamin K deficiency. We describe an infant with CDP born to a teenager with sickle cell anemia and transfusional iron overload. The mother had severe liver fibrosis, elevated liver iron concentration (34 mg Fe/g), and coagulopathy, but no gestational use of warfarin. Fetal abnormalities were attributed to vitamin K deficiency secondary to liver dysfunction from iron toxicity. Treatment of iron overload among women with sickle cell anemia of childbearing potential is important to avoid possible CDP in newborns.

A Newborn Infant with Congenital Central Hypoventilation Syndrome and Pupillary Abnormalities: A Literature Review.

We present a neonate with early onset apnea and bradycardia in the absence of primary cardiorespiratory and central nervous system disorders that eventually required chronic ventilator support starting at 6 hours of life. Molecular testing of paired-like homeobox 2b (PHOX2B) gene mutation confirmed the diagnosis of congenital central hypoventilation syndrome (CCHS). CCHS is a rare genetic disorder characterized by impaired central respiratory control with or without broad spectrum of autonomic nervous system (ANS) dysregulations. Ocular ANS dysregulation is a rare finding in CCHS individuals, and it is usually discovered later in life. However, the ophthalmic evaluation of this neonate on first day of life revealed persistent mild dilated oval pupils with limited light reactivity.

Wilms tumor in a patient with 22q11.2 microdeletion.

22q11.2 deletion syndrome is the most common microdeletion syndrome. Wilms tumor is one of the most common solid tumors in childhood yet 22q11.2 deletion and Wilms tumor only once have been reported in the same patient. Here we describe a young patient with subtle clinical findings suggestive of 22q11.2 at the time of diagnosis who subsequently developed Wilms tumor. We assert the importance of a low threshold for screening for 22q11.2 deletion and the associated phenotypes and maintaining vigilance in screening for common primary malignancies in patients with known 22q11.2 deletion.

Case report of a young child with disseminated histoplasmosis and review of hyper immunoglobulin e syndrome (HIES).

Type 1 hyper IgE syndrome (HIES), also known as Job's Syndrome, is an autosomal dominant disorder due to defects in STAT3 signaling and Th17 differentiation. Symptoms may present during infancy but diagnosis is often made in childhood or later. HIES is characterized by immunologic and non-immunologic findings such as recurrent sinopulmonary infections, recurrent skin infections, multiple fractures, atopic dermatitis and characteristic facies. These manifestations are accompanied by elevated IgE levels and reduced IL-17 producing CD3+CD4+ T cells. Diagnosis in young children can be challenging as symptoms accumulate over time along with confounding clinical dilemmas. A NIH clinical HIES scoring system was developed in 1999, and a more recent scoring system with fewer but more pathogonomonic clinical findings was reported in 2010. These scoring systems can be used as tools to help in grading the likelihood of HIES diagnosis. We report a young child ultimately presenting with disseminated histoplasmosis and a novel STAT3 variant in the SH2 domain.

Kagami-Ogata Syndrome: Case Series and Review of Literature.

Kagami-Ogata syndrome (KOS) (OMIM #608149) is a genetic imprinting disorder affecting chromosome 14 that results in a characteristic phenotype consisting of typical facial features, skeletal abnormalities including rib abnormalities described as "coat hanger ribs," respiratory distress, abdominal wall defects, polyhydramnios, and developmental delay. First identified by Wang et al in 1991, over 80 cases of KOS have been reported in the literature. KOS, however, continues to remain a rare and potentially underdiagnosed disorder. In this report, we describe two unrelated male infants with differing initial presentations who were both found to have the characteristic "coat hanger" rib appearance on chest X-ray, raising suspicion for KOS. Molecular testing confirmed KOS in each case. In addition to these new cases, we reviewed the existing cases reported in literature. Presence of polyhydramnios, small thorax, curved ribs, and abdominal wall defects must alert the perinatologist toward the possibility of KOS to facilitate appropriate molecular testing. The overall prognosis of KOS remains poor. Early diagnosis allows for counseling by a multidisciplinary team and enables parents to make informed decisions regarding both pregnancy management and postnatal care.

Case Report: An Infant With Kabuki Syndrome, Alobar Holoprosencephaly and Truncus Arteriosus: A Case for Whole Exome Sequencing in Neonates With Congenital Anomalies.

Kabuki syndrome is a rare multiple anomalies syndrome associated with mutations in KMT2D or KDM6A. It is characterized by infantile hypotonia, developmental delay and/or intellectual disability, long palpebral fissures with everted lateral third of the lower eyelids and typical facial features. Intracranial anomalies occur infrequently in patients with KS and holoprosencephaly has only been recently described. Additionally, though congenital heart diseases are common in patients with KS, to our knowledge truncus arteriosus has never been reported in a patient with KS. We present an unusual case of KS in an infant with holoprosencephaly and truncus arteriosus with partial anomalous pulmonary venous return. Duo whole exome sequencing in our patient identified a pathogenic nonsense variant in exon 10 of KMT2D (c.2782C > T; p. Gln928*) establishing the diagnosis. This report further expands the phenotypic spectrum of patients with Kabuki syndrome and emphasizes the utility of performing large scale sequencing in neonates with multiple congenital anomalies.

Effect of Whole-Genome Sequencing on the Clinical Management of Acutely Ill Infants With Suspected Genetic Disease: A Randomized Clinical Trial.

Importance: Whole-genome sequencing (WGS) shows promise as a first-line genetic test for acutely ill infants, but widespread adoption and implementation requires evidence of an effect on clinical management. Objective: To determine the effect of WGS on clinical management in a racially and ethnically diverse and geographically distributed population of acutely ill infants in the US. Design, Setting, and Participants: This randomized, time-delayed clinical trial enrolled participants from September 11, 2017, to April 30, 2019, with an observation period extending to July 2, 2019. The study was conducted at 5 US academic medical centers and affiliated children's hospitals. Participants included infants aged between 0 and 120 days who were admitted to an intensive care unit with a suspected genetic disease. Data were analyzed from January 14 to August 20, 2020. Interventions: Patients were randomized to receive clinical WGS results 15 days (early) or 60 days (delayed) after enrollment, with the observation period extending to 90 days. Usual care was continued throughout the study. Main Outcomes and Measures: The main outcome was the difference in the proportion of infants in the early and delayed groups who received a change of management (COM) 60 days after enrollment. Additional outcome measures included WGS diagnostic efficacy, within-group COM at 90 days, length of hospital stay, and mortality. Results: A total of 354 infants were randomized to the early (n = 176) or delayed (n = 178) arms. The mean participant age was 15 days (IQR, 7-32 days); 201 participants (56.8%) were boys; 19 (5.4%) were Asian; 47 (13.3%) were Black; 250 (70.6%) were White; and 38 (10.7%) were of other race. At 60 days, twice as many infants in the early group vs the delayed group received a COM (34 of 161 [21.1%; 95% CI, 15.1%-28.2%] vs 17 of 165 [10.3%; 95% CI, 6.1%-16.0%]; P = .009; odds ratio, 2.3; 95% CI, 1.22-4.32) and a molecular diagnosis (55 of 176 [31.0%; 95% CI, 24.5%-38.7%] vs 27 of 178 [15.0%; 95% CI, 10.2%-21.3%]; P < .001). At 90 days, the delayed group showed a doubling of COM (to 45 of 161 [28.0%; 95% CI, 21.2%-35.6%]) and diagnostic efficacy (to 56 of 178 [31.0%; 95% CI, 24.7%-38.8%]). The most frequent COMs across the observation window were subspecialty referrals (39 of 354; 11%), surgery or other invasive procedures (17 of 354; 4%), condition-specific medications (9 of 354; 2%), or other supportive alterations in medication (12 of 354; 3%). No differences in length of stay or survival were observed. Conclusions and Relevance: In this randomized clinical trial, for acutely ill infants in an intensive care unit, introduction of WGS was associated with a significant increase in focused clinical management compared with usual care. Access to first-line WGS may reduce health care disparities by enabling diagnostic equity. These data support WGS adoption and implementation in this population. Trail Registration: ClinicalTrials.gov Identifier: NCT03290469.

Clinical outcomes after long-term treatment with alglucosidase alfa in infants and children with advanced Pompe disease.

PURPOSE: A clinical trial was conducted to evaluate the safety and efficacy of alglucosidase alfa in infants and children with advanced Pompe disease. METHODS: Open-label, multicenter study of IV alglucosidase alfa treatment in 21 infants 3-43 months old (median 13 months) with minimal acid alpha-glucosidase activity and abnormal left ventricular mass index by echocardiography. Patients received IV alglucosidase alfa every 2 weeks for up to 168 weeks (median 120 weeks). Survival results were compared with an untreated reference cohort. RESULTS: At study end, 71% (15/21) of patients were alive and 44% (7/16) of invasive-ventilator free patients remained so. Compared with the untreated reference cohort, alglucosidase alfa reduced the risk of death by 79% (P < 0.001) and the risk of invasive ventilation by 58% (P = 0.02). Left ventricular mass index improved or remained normal in all patients evaluated beyond 12 weeks; 62% (13/21) achieved new motor milestones. Five patients were walking independently at the end of the study and 86% (18/21) gained functional independence skills. Overall, 52% (11/21) of patients experienced infusion-associated reactions; 95% (19/20) developed IgG antibodies to recombinant human lysosomal acid alpha-glucosidase; no patients withdrew from the study because of safety concerns. CONCLUSIONS: In this population of infants with advanced disease, biweekly infusions with alglucosidase alfa prolonged survival and invasive ventilation-free survival. Treatment also improved indices of cardiomyopathy, motor skills, and functional independence.

A Rare Inherited 15q11.2-q13.1 Interstitial Duplication with Maternal Somatic Mosaicism, Renal Carcinoma, and Autism.

Chromosome 15q11-q13.1 duplication is a common copy number variant associated with autism spectrum disorder (ASD). Most cases are de novo, maternal in origin and fully penetrant for ASD. Here, we describe a unique family with an interstitial 15q11.2-q13.1 maternal duplication and the presence of somatic mosaicism in the mother. She is typically functioning, but formal autism testing showed mild ASD. She had several congenital anomalies, and she is the first 15q Duplication case reported in the literature to develop unilateral renal carcinoma. Her two affected children share some of these clinical characteristics, and have severe ASD. Several tissues in the mother, including blood, skin, a kidney tumor, and normal kidney margin tissues were studied for the presence of the 15q11-q13.1 duplication. We show the mother has somatic mosaicism for the duplication in several tissues to varying degrees. A growth competition assay in two types of stem cells from duplication 15q individuals was also performed. Our results suggest that the presence of this interstitial duplication 15q chromosome may confer a previously unknown growth advantage in this particular individual, but not in the general interstitial duplication 15q population.

Treatment of diffuse basal cell carcinomas and basaloid follicular hamartomas in nevoid basal cell carcinoma syndrome by wide-area 5-aminolevulinic acid photodynamic therapy.

OBJECTIVE: To report the use of wide-area 5-aminolevulinic acid photodynamic therapy to treat numerous basal cell carcinomas (BCCs) and basaloid follicular hamartomas (BFHs). DESIGN: Report of cases. SETTING: Roswell Park Cancer Institute. Patients Three children with BCCs and BFHs involving 12% to 25% of their body surface areas. Interventions Twenty percent 5-aminolevulinic acid was applied to up to 22% of the body surface for 24 hours under occlusion. A dye laser and a lamp illuminated fields up to 7 cm and 16 cm in diameter, respectively; up to 36 fields were treated per session. MAIN OUTCOME MEASURES: Morbidity, patient response, and light dose-photodynamic therapy response relationship and durability. RESULTS: Morbidity was minimal, with selective phototoxicity and rapid healing. After 4 to 7 sessions, with individual areas receiving 1 to 3 treatments, the patients had 85% to 98% overall clearance and excellent cosmetic outcomes without scarring. For laser treatments, a sigmoidal light dose-response relationship predicted more than 85% initial response rates for light doses 150 J/cm(2) or more. Responses were durable up to 6 years. Conclusion 5-Aminolevulinic acid photodynamic therapy is safe, well tolerated, and effective for extensive areas of diffuse BCCs and BFHs and appears to be the treatment of choice in children.

The interstitial duplication 15q11.2-q13 syndrome includes autism, mild facial anomalies and a characteristic EEG signature.

Chromosomal copy number variants (CNV) are the most common genetic lesion found in autism. Many autism-associated CNVs are duplications of chromosome 15q. Although most cases of interstitial (int) dup(15) that present clinically are de novo and maternally derived or inherited, both pathogenic and unaffected paternal duplications of 15q have been identified. We performed a phenotype/genotype analysis of individuals with interstitial 15q duplications to broaden our understanding of the 15q syndrome and investigate the contribution of 15q duplication to increased autism risk. All subjects were recruited solely on the basis of interstitial duplication 15q11.2-q13 status. Comparative array genome hybridization was used to determine the duplication size and boundaries while the methylation status of the maternally methylated small nuclear ribonucleoprotein polypeptide N gene was used to determine the parent of origin of the duplication. We determined the duplication size and parental origin for 14 int dup(15) subjects: 10 maternal and 4 paternal cases. The majority of int dup(15) cases recruited were maternal in origin, most likely due to our finding that maternal duplication was coincident with autism spectrum disorder. The size of the duplication did not correlate with the severity of the phenotype as established by Autism Diagnostic Observation Scale calibrated severity score. We identified phenotypes not comprehensively described before in this cohort including mild facial dysmorphism, sleep problems and an unusual electroencephalogram variant. Our results are consistent with the hypothesis that the maternally expressed ubiquitin protein ligase E3A gene is primarily responsible for the autism phenotype in int dup(15) since all maternal cases tested presented on the autism spectrum.

A triple threat: Down syndrome, congenital central hypoventilation syndrome, and Hirschsprung disease.

Down syndrome (DS) is recognized by characteristic facial features, intellectual disability, and an increased risk for cardiac malformations and duodenal atresia. Recently, Hirschsprung disease (HSCR), or congenital aganglionic megacolon, has been seen more often among patients with DS. Given the systemic nature of DS-related features, it is natural to attribute neonatal complications to the chromosomal aberration. We describe a biracial male infant with DS who had significantly delayed defecation and required continuous ventilator support, but had no primary cardiac or lung disease. Subsequent evaluations confirmed total colonic aganglionosis. Because we were unable to safely extubate the infant, a diagnosis of congenital central hypoventilation syndrome (CCHS) was considered and confirmed by molecular analysis of the PHOX2B gene, revealing a heterozygous polyalanine repeat-expansion mutation containing 27 repeats (normal gene contains 20 repeats). HSCR coexisting with CCHS is known as Haddad syndrome. This is the first reported case with co-occurrence of DS, CCHS, and HSCR.

Goltz syndrome: report of two severe cases.

Goltz syndrome is a rare, X-linked dominant congenital disorder with abnormalities in derivatives of each of the three embryonic germ layers. Its clinical phenotype varies widely, ranging from isolated skin defects to absence of limbs and/or organs. The rarity and wide range of presentation contribute to delayed or missed diagnosis.