Familial synspondylism: progressive scoliosis and multiple hernias in a kinship.

A new genetic syndrome is reported of congenital lordoscoliosis due to lumbar segmentation defects and incomplete formation of lumbar vertebrae. The defect arose as a spontaneous mutation and was transmitted in an autosomal dominant fashion. The kindred included a mother and her three offspring. These affected individuals had several dysmorphic features including cavus feet and micrognathia. In addition the syndrome was associated with multiple hernias including inguinal, ventral, and diaphragmatic. These associated problems led to the early death of the first child at age 7 months. The lumbar scoliosis was already evident by that time. The progressive nature of the scoliosis was documented, especially in one child who was lost to follow-up and who was initially seen with a severe spinal deformity. Surgical management was required in members of the kindred, but because of differences in age and severity at the time of surgery, the techniques varied.

Dystonia with motor delay in compound heterozygotes for GTP-cyclohydrolase I gene mutations.

Mutations in the GTP-cyclohydrolase I (GCH) gene have been identified as a cause of two disorders: autosomal dominant hereditary progressive dystonia/dopa-responsive dystonia (HPD/DRD) and autosomal recessive GCH-deficient hyperphenylalaninemia (HPA). Detailed clinical descriptions and genetic analysis of patients with phenotypes intermediate between HPD/DRD (mild) and GCH-deficient HPA (severe) have not been reported. We conducted genomic DNA sequencing of the GCH gene in two patients (Cases 1 and 2) manifesting generalized dystonia responsive to levodopa and severe developmental motor delay. In the pedigree of Patient 1, there were HPD/DRD patients in three generations preceding the index case. Patients 1 and 2 were compound heterozygotes with maternally and paternally transmitted mutations in the coding region of the GCH gene. In both compound heterozygotes, tetrahydrobiopterin (BH4) levels in cerebrospinal fluid were lower than those in HPD/DRD. Administration of BH4, in addition to levodopa, further improved the symptomatology of Patient 1. Our data demonstrate a new phenotype of GCH deficiency associated with compound heterozygosity for GCH gene mutations and suggest the usefulness of combined BH4 and levodopa therapy for this disorder.

Oral phenylalanine loading in dopa-responsive dystonia: a possible diagnostic test.

To determine if there is abnormal phenylalanine and biopterin metabolism in patients with dopa-responsive dystonia (DRD), we measured plasma levels of phenylalanine, tyrosine, biopterin, and neopterin at baseline, and 1, 2, 4, and 6 hours after an oral phenylalanine load (100 mg/kg). Seven adults with DRD, two severely affected children with DRD, and nine adult controls were studied. All patients had phenylalanine and tyrosine concentrations within the normal range at baseline. In the adult patients, phenylalanine levels were higher than in controls at 2, 4, and 6 hours post-load (p < 0.0005); tyrosine concentrations were lower than control levels at 1, 2, and 4 hours post-load (p < 0.05). Phenylalanine to tyrosine ratios were elevated in patients at all times post-load (p < 0.0005). Biopterin levels in the patients were decreased at baseline and 1, 2, and 4 hours post-load (p < 0.005). Pretreatment with tetrahydrobiopterin (7.5 mg/kg) normalized phenylalanine and tyrosine profiles in two adult patients. In the children with DRD, phenylalanine to tyrosine ratios were slightly elevated at baseline. Following phenylalanine loading, the phenylalanine profiles were similar to those seen in the adult patients but there was no elevation in plasma tyrosine. Baseline biopterin levels were lower in the children with DRD than in the adult patients or the controls and there was no increase in biopterin post-load. In both the children and adults with DRD, neopterin concentrations did not differ from control values at baseline or after phenylalanine load. The results are consistent with decreased liver phenylalanine hydroxylase activity due to defective synthesis of tetrahydrobiopterin in patients with DRD. The findings show that a phenylalanine load may be useful in the diagnosis of this disorder.

Abnormal head MRI in a neurologically normal boy with hypomelanosis of Ito.

We report on an 8.5-year-old boy with hypomelanosis of Ito (HI) who has an abnormal MRI of the brain but is neurologically normal. There have been many reports of abnormal brain imaging studies in patients with HI, but all reported patients have had abnormal neurologic findings or symptoms. Our patient has had serial, stable head MRI white matter changes and has remained neurologically normal without any neurologic sequelae.

Chondrodysplasia punctata, humero-metacarpal type: a second case.

We report on a boy with symmetrical rhizomelic shortness of the upper limbs and punctate epiphyseal calcifications noted at birth. Radiographs documented short and wide humeri, symmetrical brachymetacarpy, coronal clefts of the veretebrae, and punctate calcifications in the spine, sacrum, shoulder, feet, and trachea. Borochowitz [1991] described a similar patient with an apparently new syndrome of chondrodysplasia punctata (CP), distinct from previously described forms. He suggested the term "chondrodysplasia punctata, humero-metacarpal (HM)" type. We present our patient as a second case of this form of CP.

Chromosome 22q11.2 deletion in a boy with Opitz (G/BBB) syndrome.

This report is on a 14-month-old boy with manifestations of Opitz (G/BBB) syndrome in whom a 22q11.2 deletion was found. Deletion analysis was requested because of some findings in this patient reminiscent of velocardiofacial (VCF) syndrome. The extent of aspiration and of respiratory symptoms in this child is not usually seen in VCF syndrome. Opitz syndrome maps to at least two loci, one on Xp, the other on 22q11.2.

Vascular ring leading to tracheoesophageal compression in a patient with Rubinstein-Taybi syndrome.

Mediastinal vascular rings cause tracheoesophageal obstruction, resulting in respiratory symptoms and dysphagia in children. Although a large number of children with Rubinstein-Taybi syndrome have frequent respiratory infections and feeding difficulties, there has been no firmly established association between this syndrome and the occurrence of vascular rings. We report on a patient with Rubinstein-Taybi syndrome who had a vascular ring. Since there was a previous report of a similar ring in a child with Rubinstein-Taybi syndrome, we suggest there may be an association between Rubinstein-Taybi syndrome and vascular rings.

Long-term follow-up of cutaneous changes in siblings with mandibuloacral dysplasia who were originally considered to have hereditary sclerosing poikiloderma.

Mandibuloacral dysplasia is a rare syndrome characterized by mandibular hypoplasia, delayed cranial suture closure, dysplastic clavicles, abbreviated, club-shaped terminal phalanges, acroosteolysis, atrophy of the skin over the hands and feet, and poikilodermatous skin changes. We describe the cases of two siblings with features of mandibuloacral dysplasia who as children were considered to have hereditary sclerosing poikiloderma. On their reevaluation as adults, the clinical features of their condition were perceived to be compatible with mandibuloacral dysplasia.

Recurrent lambdoid synostosis within two families.

We report on 2 families with multiple members who have proven or suspected lambdoid craniosynostosis. In one family the lambdoid suture was unilaterally involved in one sib, and bilaterally in the other. In the second family the propositus had unilateral lambdoid synostosis and his twin sisters each had bilateral lambdoid synostosis. Both families had another distant relative, a maternal grandmother in the first and paternal uncle in the second, who were also reported to have posterior plagiocephaly. We report these families as evidence for genetic transmission of a craniosynostotic trait which has only been rarely reported previously.

Analysis of phenotypic features and FGFR2 mutations in Apert syndrome.

A phenotypic and genotypic survey was conducted on 36 Apert syndrome patients. In all but one patient, an FGFR2 mutation, either S252W or P253R, was found in exon IIIa (exon U or 7). The frequency was 71% and 26%, for the mutations S252W and P253R, respectively. These mutations occur in the linker region between immunoglobulin-like domains II and III, which are involved in activation of the receptor by ligand binding and dimerization. The fact that one patient did not have a mutation in the same exon suggests further genetic heterogeneity in Apert syndrome. The frequencies of occurrence or means for measurements of 29 different clinical features (including severity of craniofacial features, syndactyly of the hands and feet, and multisystem involvement) were determined for all patients and for the two subgroups defined by their mutations. Comparison between the subgroups for the different clinical features was performed and suggested no statistically significant differences. These results are not unexpected, because the two common mutations for Apert syndrome alter FGFR2 at adjacent amino acids that are likely to have similar biological, and therefore phenotypic, consequences.

Neuroectodermal (CHIME) syndrome: an additional case with long term follow up of all reported cases.

A new neuroectodermal syndrome (designated CHIME syndrome) was described in 1983 with a total of four patients reported, it is presumed to be an autosomal recessive disorder because of recurrence in sibs. The main features include ocular colobomas, congenital heart disease, early onset migratory ichthyosiform dermatosis, mental retardation, conductive hearing loss, seizures, and typical facial features. We report a fifth child with the condition, confirming the unique nature of the condition. Long term follow up information on this patient, as well as the previously described cases, provides information regarding the outcome for these patients, which includes general good health, severe mental retardation, seizures that worsen after puberty, conductive hearing loss, and chronic migratory ichthyosiform skin rash without scarring.

Long-chain 3-hydroxyacyl-coenzyme A dehydrogenase (L-CHAD) deficiency in a patient with the Bannayan-Riley-Ruvalcaba syndrome.

Bannayan-Riley-Ruvalcaba syndrome (BRRS) is an autosomal dominant condition of macrocephaly in combination with lipomas/hemangiomas, hypotonia, developmental delay, and a lipid myopathy. The etiology of the lipid storage myopathy has been unclear. We describe a black boy with findings of BRRS who also has a defect in long-chain fatty acid oxidation expressed in cultured skin fibroblasts as a deficiency of long-chain-L-3-hydroxyacyl-CoA dehydrogenase (L-CHAD). He also has an abnormal brain MRI and increased size of both lower limbs. We present this child because of his unusual combination of findings, and postulate that L-CHAD deficiency may be the cause of the lipid myopathy in BRRS.

Choanal atresia in a patient with the deletion (9p) syndrome.

We report on a child with choanal atresia and deletion 9p. A review of the literature documented one previous instance of choanal atresia in a patient with del(9p). Choanal atresia may be part of the spectrum of malformations in the deletion (9p) syndrome and its presence should prompt a search for this particular deletion as part of the differential diagnosis.

Epidermal naevi and bullous aplasia cutis congenita in a neonate.

The case of a neonate with cutaneous lesions consistent with epidermal naevi is presented. In addition to typical epidermal naevi, this baby had an unusual, bullous form of aplasia cutis congenita. Although aplasia cutis has been described as bullous and has been found in association with the epidermal naevus syndrome, both of these occurrences are rare in medical publications. This case illustrates an unusual presentation of epidermal naevi with bullous aplasia cutis congenita and raises difficult diagnostic and counselling issues.

Mosaicism in chorionic villus sampling.

Although chromosomal mosaicism is encountered frequently in CVS, it is most often restricted to the extraembryonic tissues. Counseling before CVS should include a discussion of the frequency and significance of placental mosaicism. Patients seeking information about the procedure need to be aware of the slight but not negligible possibility of the need for additional follow-up studies. Additional studies may involve additional risks with emotional and psychological sequelae. Ultimately, no prenatal procedure or combination of procedures can provide 100% accuracy in excluding mosaicism once the issue has been raised. When the mosaicism is felt to be confined to the placenta, counseling should probably address the potential increased risk for pregnancy complication, such as miscarriage and IUGR, with appropriate follow-up of the pregnancy, especially in the third trimester. Excluding the issue of mosaicism, the predictive value of cytogenetic diagnosis after CVS is equivalent to that of amniocentesis. In addition, CVS provides this information at an earlier time in the pregnancy than does amniocentesis. The majority of patients electing CVS (98% or more) will not have to deal with these complicated issues. It is hoped that an increasing cumulative experience with CVS mosaicism will help differentiate low- from high-risk situations. At the present time, however, there are insufficient and inconsistent data with which to accurately assess the risks associated with placental mosaicism. Most of the available literature concludes that additional, more focused studies, including long-term follow-up, are needed to help elucidate a better understanding of these issues.

Frontonasal dysplasia in two successive generations.

Frontonasal dysplasia is thought to be a sporadic condition limited to the face and head. We describe a family from the Bahamas in which a mother, 2 of her children, and the mother's brother have variable manifestations of frontonasal dysplasia. The mother has extremely mild expression, but her brother and 2 sons are more severely affected. Besides polydactyly no other birth defects were noted in any other relatives. The pedigree is consistent with autosomal or X-linked dominant inheritance. A description of each patient is presented along with a discussion of the genetic counseling issues and review of the literature for other possibly familial cases of frontonasal dysplasia.

Follow-up of pregnancies complicated by placental mosaicism diagnosed by chorionic villus sampling.

Thirty-nine (2.3 per cent) of 1724 chromosome studies from diagnostic chorionic villus samplings (CVS) done between 1983 and 1990 showed either level III (true) mosaicism (1.2 per cent) or level II (pseudo-) mosaicism (1.1 per cent) for chromosomal aneuploidy. Follow-up information on these 39 pregnancies was collected from questionnaires to families, paediatricians, and obstetricians. For all cases in which the pregnancy was continued and further testing was accomplished, the mosaicism was felt to be confined to the placenta. As compared with a control group of pregnancies evaluated by CVS with normal karyotypes, there was no increased incidence of pregnancy loss, congenital malformations, or developmental delay in the infants. Although intrauterine growth retardation occurred in several of the level III mosaic cases, adequate catch-up growth has been demonstrated.

Interstitial deletion of 8q13.3-->22.1 associated with craniosynostosis.

We report on a 3-year-old girl who has an interstitial deletion of chromosome 8q [46,XX,del(8)(q13.3q22.1)]. She has severe mental retardation and minor anomalies in addition to lambdoidal synostosis. This is the first report of craniosynostosis in association with this chromosomal deletion. The manifestations of our patient are compared to those of previously reported patients with similar deletions.

Postnatal placental confirmation of trisomy 2 and trisomy 16 detected at chorionic villus sampling: a possible association with intrauterine growth retardation and elevated maternal serum alpha-fetoprotein.

Detection of trisomy 2 and trisomy 16 mosaicism through chorionic villus sampling (CVS) is not an infrequent finding. We describe here two cases, one of non-mosaic trisomy 2 and the other of high level mosaicism for trisomy 16. Amniocentesis in both cases demonstrated non-mosaic 46,XY karyotypes. Each pregnancy continued to delivery of liveborn, normal-appearing boys; both pregnancies were complicated by severe intrauterine growth retardation (IUGR). Postnatal studies of placental biopsies in both cases confirmed the original CVS findings, whereas cord blood karyotypes were normal in both boys. Both children have demonstrated adequate catch-up growth.

Allelic loss on chromosome 11 in hereditary and sporadic tumors related to familial multiple endocrine neoplasia type 1.

Familial multiple endocrine neoplasia type 1 (FMEN1) is an autosomal dominant disorder characterized by tumors of the parathyroid glands, pancreatic islets, and anterior pituitary. The gene for this disease maps to chromosome 11q12-11q13, and allelic loss in this region has been shown in both sporadic and FMEN1-related parathyroid tumors. FMEN1-related pancreatic islet tumors, and rarely in sporadic anterior pituitary tumors. We tested for allelic loss at 7 loci on chromosome 11 in 17 tumors outside the parathyroid. We found loss of heterozygosity in 2 of 2 FMEN1-related benign pancreatic islet tumors but in none of 8 informative sporadic islet tumors (P = 0.02) including 5 malignant gastrinomas. Of 3 islet tumors from patients who had some but not all features of FMEN1, one showed allelic loss for 5 of 5 informative restriction fragment length polymorphisms, and the other 2 retained heterozygosity for all informative markers. A bronchial carcinoid from an FMEN1 patient and 3 sporadic anterior pituitary tumors showed no allelic loss. These data provide new evidence that many sporadic pancreatic islet neoplasms, even when malignant, do not develop through homozygous inactivation of the MEN1 gene.