Fryns syndrome: an autosomal recessive disorder associated with craniofacial anomalies, diaphragmatic hernia, and distal digital hypoplasia.

Fryns syndrome is an autosomal recessive, genetically determined condition with variable expression, which includes abnormal facial features, diaphragmatic hernia, distal limb abnormalities, and malformations of the cardiovascular, gastrointestinal, genitourinary, and central nervous systems. Five cases of children with Fryns syndrome, including an example of familial recurrence and a case of long-term survival, are described. This report brings to 25 the number of cases reported in the literature and further serves to illustrate the clinical variability of this disorder.

PHAVER syndrome: an autosomal recessive syndrome of limb pterygia, congenital heart anomalies, vertebral defects, ear anomalies, and radial defects.

We have studied 2 sibs with vertebral, radial, congenital heart, and ear defects. The second patient also had limb pterygia and meningomyelocele. The abnormalities in these two sibs are seen in the VATER association; however, distinguishing these cases from the VATER association are the findings of pterygia, meningomyelocele, and probable autosomal recessive inheritance. We propose the acronym PHAVER syndrome for limb pterygia, heart defects, autosomal recessive inheritance, vertebral defects, ear anomalies and radial defects. This represents a new autosomal recessive disorder with phenotypic variability.

Ullrich-Turner syndrome and neurofibromatosis-1.

There is a well-known association between neurofibromatosis-1 (NF1) and Noonan syndrome-like manifestations, including short stature, short broad neck, and hypertelorism. These anomalies are thought to be due to variable expression of the NF1 gene. We report on two girls with NF1 who were found to have the Ullrich-Turner syndrome. Case 1, a 12-year-old white girl, was followed in a Neurofibromatosis Clinic because of multiple café-au-lait spots and a family history of NF1 in her mother and sister. On examination, she had short stature, hypertelorism, and short neck with low posterior hairline. Karyotype was 86% 46,XY/14% 45,X. Case 2, the first child of a woman with NF1, presented at birth with lymphedema of hands and feet and a short broad neck. Karyotype was 45,X. At age 23 months she was short, had epicanthic folds, hypertelorism, narrow palate, right simian crease, 19 café-au-lait spots, and axillary freckling. We conclude that chromosome studies should be performed in girls with NF1 who have short stature and Noonan- or Ullrich-Turner-like findings. Dilemmas raised by the dual diagnoses of NF1 and Ullrich-Turner syndrome include potential risks of growth hormone therapy and estrogen replacement therapy.

Progressive laryngotracheal stenosis with short stature and arthropathy.

Laryngotracheal stenosis is rare in adults, especially in the absence of a malignancy. It is most commonly caused by fibrosis following endotracheal intubation or tracheal trauma. Other conditions causing progressive airway narrowing include the mucopolysaccharidoses and autoimmune disorders. With the exception of storage diseases, there are no well-defined genetic disorders with progressive airway narrowing as a common complication. We have evaluated three unrelated individuals with this potentially life-threatening finding, all of whom have a previously unrecognized condition. Each patient had short stature and joint stiffness with no evidence for infectious, inflammatory, or metabolic diseases as a cause of their condition. None of our patients had clinical findings indicative of known skeletal dysplasias or storage diseases. They had minor facial anomalies which included deeply set eyes, bushy eyebrows, and flat midface. Given the unique findings of our patients including adult onset critical tracheal stenosis, short stature, progressive joint limitation, and distinct facial anomalies, we conclude that they have a previously undescribed condition.

Brachmann-de Lange syndrome with normal IQ.

The Brachmann-de Lange syndrome is a disorder with a high degree of clinical variability, generally associated with moderate to severe mental retardation. To date, 7 previous cases of Brachmann-de Lange syndrome with normal intelligence (IQ > 70) have been described. We report the eighth case of Brachmann-de Lange syndrome with normal intelligence. In reviewing the literature, consistent clinical manifestations seen in these 8 patients that are of prognostic value are the absence of significant limb anomalies and birth weight > 2,500 g.

Dominant syndrome with isolated cryptophthalmos and ocular anomalies.

We report on a mother and daughter with nonsyndromal cryptophthalmos. Both patients have additional ocular anomalies, including microphthalmia, retinal dysplasia, and Peters anomaly. The periocular and lid changes seen in these individuals are distinct from those seen in typical cryptophthalmos. The apparent dominant mode of inheritance in this family distinguishes this condition from autosomal recessive isolated cryptophthalmos and from the Fraser or cryptophthalmos syndrome.

Autosomal recessive Robinow-like syndrome with anterior chamber cleavage anomalies.

We describe 2 sisters with short stature, mesomelic brachymelia, macrocephaly, hypoplastic genitalia, and anterior chamber cleavage anomalies. Many of their manifestations have been described in individuals with Robinow syndrome; however, the anterior chamber cleavage anomalies seen in both girls, hydrocephalus seen in the younger sister, and apparent autosomal recessive inheritance do not characterize the Robinow syndrome. The syndrome present in these sisters most likely represents a previously undescribed autosomal recessive syndrome.

Thoracic tumors in children with neurofibromatosis-1.

Thoracic tumors have been infrequently reported as a complication of neurofibromatosis-1 (NF1). To determine the prevalence and clinical features of thoracic tumors seen in children with NF1, we reviewed medical records and imaging studies for a group of 260 pediatric patients with NF1 followed in a multidisciplinary NF Center. Extrapleural thoracic tumors were seen in nine patients with NF1, corresponding to a prevalence of 3.5% in this hospital-based series of patients. Pathological studies of the tumors demonstrated plexiform neurofibroma in four cases and neurofibrosarcoma in one case. The remaining four cases were suspected to be plexiform neurofibroma based on clinical features but have not been confirmed histologically. Three patients presented with symptoms of chest pain, syncope, or wheezing; six patients were asymptomatic at the time of diagnosis of the tumors. Physical findings frequently found in patients with thoracic tumors were scoliosis (especially focal scoliosis) and visible plexiform neurofibromas of the neck. We conclude that NF1 patients presenting with any of these signs and symptoms should be screened for thoracic tumors with chest X-ray and magnetic resonance imaging as needed. It is unknown whether screening asymptomatic NF1 patients with chest X-rays on a regular basis will result in an improved outcome.

Patient with craniosynostosis and marfanoid phenotype (Shprintzen-Goldberg syndrome) and cloverleaf skull.

Marfanoid phenotype with craniosynostosis (Shprintzen-Goldberg syndrome) is a rare disorder previously described in only 5 patients. We report on the sixth known patient with this condition. The findings which distinguish our patient from others reported previously are that she was ascertained prenatally as having a cloverleaf skull; this is the first female patient described with this condition. Postnatally, she presented with arachnodactyly, camptodactyly, and clover-leaf skull. Imaging studies of the brain documented microcephaly with malformed brain, hydrocephaly, and hypoplasia of the corpus callosum. She also had choanal atresia and stenosis, a clinical finding previously reported only once, in this disorder.

New autosomal recessive syndrome of sparse hair, osteopenia, and mental retardation in Mennonite sisters.

We report on 2 Mennonite sisters with a syndrome of sparse hair, osteopenia, mental retardation, minor facial abnormalities, joint laxity, and hypotonia. Their asymptomatic consanguineous parents (inbreeding coefficient F = 1/64) have 6 other offspring, 3 of whom died in infancy of type II osteogenesis imperfecta (OI), and 3 of whom are normal. We analyzed collagens synthesized by cultured fibroblasts from these 2 sisters and their parents and detected no major abnormalities. Results of chromosomal and metabolic evaluations including amino acid analysis of plasma, urine, and hair were unremarkable. A literature search and survey of a computerized syndrome identification database did not disclose an identical phenotype. The sisters bear superficial resemblance to several known syndromes which we excluded on clinical and/or biochemical grounds. We conclude that they represent a new autosomal recessive syndrome, distinct from type II OI and perhaps unique to the Mennonite population or to this particular family.

New insights into the phenotypes of 6q deletions.

Deletions of chromosome 6q are rare. We report 3 new patients with 6q deletions. Case 1 is a male with an interstitial deletion [del(6)(q13q14.2)], hypotonia, speech delays, and minor anomalies. Case 2 is a male with an interstitial deletion [del(6)(q16.2q22.32)] and malformations, including truncus arteriosus and bilateral oligodactyly. Case 3 is a male with a terminal deletion [del(6)(q25.2)] with retinal pits, hydrocephalus, atrioventricular canal, and hydronephrosis. The findings in our patients and those from 57 previously reported cases demonstrated 3 phenotypic groups associated with 6q deletions. Group A [del(6)(q11-q16)] had a high incidence of hernias, upslanting palpebral fissures, and thin lips with lower frequency of microcephaly, micrognathia, and heart malformations. Group B [del(6)(q15-q25)] was associated with increased intrauterine growth retardation, abnormal respiration, hypertelorism, and upper limb malformations. Group C [del(6)(q25-qter)] was associated with retinal abnormalities, cleft palate, and genital hypoplasia. The only universal finding among all patients with 6q deletions was mental retardation. Other findings common to all 3 groups included ear anomalies (90%), hypotonia (82%), and postnatal growth retardation (68%).

Neurodevelopmental profile of infants and toddlers with oculo-auriculo-vertebral spectrum and the correlation of prognosis with physical findings.

We studied the neurodevelopmental profile of infants and toddlers with oculo-auriculo-vertebral spectrum (OAV) and determined if certain physical manifestations were indicative of a poor neurodevelopmental prognosis. Twenty-four patients with OAV, aged birth to 57 months, were seen in the Department of Medical Genetics at Children's National Medical Center for multidisciplinary evaluations, including neurodevelopmental assessments. Fifty-eight percent of these children scored more than 2 standard deviations below the mean in at least one domain of development. There was no difference in developmental outcome of boys versus girls, children affected unilaterally on the right side versus left side, and those with severe clinical manifestations versus those with a milder form. Children with OAV and abnormal muscle tone had lower cognitive, gross motor, and expressive language scores (P = 0.05, P = 0.002, and P = 0.02, respectively). Those affected bilaterally had lower cognitive, fine motor, receptive language, and expressive language scores (P = 0.06, P = 0.03, P = 0.03, P = 0.02, respectively). Children with cervical spine abnormalities had lower cognitive, fine motor, and expressive language scores (P = 0.02, P = 0.04, and P = 0.04, respectively). We conclude that infants and toddlers with OAV are at increased risk for neurodevelopmental delay, especially those with abnormal muscle tone, bilateral involvement, and cervical vertebral anomalies. The complexity of the neurodevelopmental problems is strongly suggestive of central nervous system disturbances. Patients with OAV need comprehensive evaluation by a multidisciplinary team to define potential neurodevelopmental delays, allow for early intervention services, and promote an optimal developmental outcome.

Loss of the N-myc oncogene in a patient with a small interstitial deletion of the short arm of chromosome 2.

To our knowledge, only four previous cases of distal chromosome 2p deletions exist in the literature. We present a patient with minor facial anomalies who had a distal interstitial deletion of the short arm of chromosome 2, del(2)(p24.2p25.1). This patient had many features seen in other patients with distal 2p deletion including short stature, "rectangular" facies, microcephaly, hypotonia, and mental retardation. This patient also has sensorineural hearing loss which has been described in one other patient with a similar deletion. The N-myc oncogene has been mapped to 2p24. By fluorescence in situ hybridization using a cDNA probe for the N-myc oncogene, this patient was found to have a deletion of the N-myc oncogene. This confirms the previous map location for N-myc.

Variation in microdeletions of the cyclic AMP-responsive element-binding protein gene at chromosome band 16p13.3 in the Rubinstein-Taybi syndrome.

Most reported microdeletions of the CREB-binding protein (CBP) gene in the Rubinstein-Taybi syndrome (RTS) were detected by fluorescence in situ hybridization (FISH) with a single cosmid probe specific to the 3' region of the gene. In order to test the hypothesis that the rate of microdeletion-positive cases would be greater if the entire gene was evaluated, we performed FISH on 66 patients with an established diagnosis of RTS, using a panel of five cosmids that span the CBP gene. Five of 66 patients had deletions by FISH (9%), consistent with those rates reported in various series that ranged between 3-25%. Among our cases, different deletions were observed; one was deleted for the 5' but not the 3' region of the CBP gene (case 055). Other deletions included a total CBP deletion extending from the 5' through the 3' region (case 017), a deletion of all but the 5' region (cases 006 and 060), and an interstitial deletion in the 3' region (case 028). Fine breakpoint mapping with additional cosmid and yeast artificial chromosome (YAC) constructs was performed on these patients. The findings of a partial 5' deletion and of interstitial deletions of the CBP gene add to the known spectrum of mutations of this gene in RTS and demonstrate the need for evaluation of the entire CBP gene region for deletions rather than only the 3' region in RTS patients. These results further suggest that the true rate of microdeletion across the CBP gene detectable by FISH has yet to be established firmly. No phenotypic differences between partial deletion, complete deletion, and nondeletion patients were observed, supporting a haploinsufficiency model for RSTS.

Partial trisomy 1q with growth hormone deficiency and normal intelligence.

We present two sibs with partial trisomy 1 (q31.1-q32.1) due to a familial insertion. Patient 1 is a girl who presented at age 9 months with minor anomalies, short stature, and normal psychomotor development. Karyotype was 46,XX,der(4)ins(4;1) (p14;q31.1q32.1)pat. The father had a balanced inverted insertion of 1q into 4p, with karyotype 46,XY,ins(4;1)(p14;q31.1q32.1). At age 5 years, patient 1 was found to have short stature with documented growth hormone deficiency and ectopic pituitary. Her growth velocity responded well to treatment with growth hormone. Cognitive testing at 5 9/12 years showed normal intelligence with an IQ of 90. Patient 2, the brother of patient 1, presented with intrauterine growth retardation. He has the same chromosomal insertion as his sister, with partial trisomy 1q. We suggest that there is a recognizable phenotype of trisomy 1(q31.1-q32.1) which includes prenatal and postnatal growth retardation, narrow palpebral fissures, microphthalmia, microstomia, pituitary abnormalities, and normal intelligence in some individuals.

Deletions and microdeletions of 22q11.2 in velo-cardio-facial syndrome.

Velo-cardio-facial syndrome (VCFS), an autosomal dominant disorder, is characterized by cleft palate, cardiac defects, learning disabilities and a typical facial appearance. Less frequently, VCFS patients have manifestations of the DiGeorge complex (DGC) including hypocalcemia, hypoplastic or absent lymphoid tissue and T-cell deficiency suggesting that these 2 conditions share a common pathogenesis. Here, we report the results of cytogenetic and molecular studies of 15 VCFS patients. High-resolution banding techniques detected an interstitial deletion of 22q11.21-q11.23 in 3 patients. The remaining 12 patients had apparently normal chromosomes. Molecular analysis with probes from the DiGeorge Chromosome Region (DGCR) within 22q11 detected DNA deletions in 14 of 15 patients. In 2 families, deletions were detected in the affected parent as well as the propositus suggesting that the autosomal dominant transmission of VCFS is due to segregation of a deletion. Deletions of the same loci previously shown to be deleted in patients with DGC explains the overlapping phenotype of VCFS and the DGC and supports the hypothesis that the cause of these two disorders is the same.

Cytogenetic evaluation of fetal death: the role of amniocentesis.

Fetal death can be associated with chromosomal abnormalities. Because of the degree of tissue maceration and autolysis seen in stillborn fetuses, it is often impossible to successfully culture these tissues for cytogenetic studies. We performed genetic amniocentesis in four cases of fetal death and were successful in obtaining cytogenetic results in all four, whereas the culture of fetal tissues for cytogenetics was successful in only one case. Chromosomal abnormalities were found in three of the four cases, including two fetuses with Down's syndrome and one fetus with Turner's syndrome. Because of the importance of cytogenetic studies in most cases of fetal death, we recommend amniocentesis at the time of diagnosis rather than waiting for delivery of fetal tissues, when postmortem changes may make it impossible to successfully culture fetal cells.

Airway obstruction in the Pierre Robin sequence.

Airway obstruction and feeding difficulties vary among patients with Pierre Robin sequence (PRS). Treatment is challenging and the appropriate management may not be readily identified, leading to delay in securing the airway. A retrospective review of 90 children with PRS was done to identify subgroups at a higher risk of developing severe airway obstruction using oxygen and apnea monitoring, sleep studies, and response to treatment. Patients with isolated PRS (group I, 27 patients) and Stickler syndrome (group II, 32 patients) do not suffer from debilitating airway and feeding difficulties when compared to those with unique syndromes (group III, 16 patients) and recognized named syndromes (group IV, 15 patients). Feeding difficulties were universal with the severity proportional to airway obstruction. Aggressive intervention should be considered early in group III and IV patients.

Ectrodactyly, diaphragmatic hernia, congenital heart defect, and agenesis of the corpus callosum.

A unique case of a female born with four major malformations, ectrodactyly, diaphragmatic hernia, ventricular septal defect, and agenesis of the corpus callosum is reported. The patient had a normal birth weight, normal head circumference and a normal karyotype. There was no significant facial dysmorphism. The family history was unremarkable for birth defects, recurrent pregnancy loss, limb anomalies or consanguinity. We propose that this represents a new constellation of multiple malformations.

Yogurt. Contributory factor in development of nutritional rickets.

Vitamin D deficient rickets occurred in a 15-month-old black girl for whom yogurt had been substituted for milk products. Investigation determined that commercially available yogurt contains no vitamin D, and that this fact is not generally recognized by lay persons and health professionals. Use of yogurt as a major source of nutritional intake in infants and young children may be a contributory factor in development of vitamin D deficiency rickets.