Fibroblast growth factor receptor 2 mutations in Beare-Stevenson cutis gyrata syndrome.

Beare-Stevenson cutis gyrata syndrome (MIM 123790) is an autosomal dominant condition characterized by the furrowed skin disorder of cutis gyrata, acanthosis nigricans, craniosynostosis, craniofacial dysmorphism, digital anomalies, umbilical and anogenital abnormalities and early death. Many of these features are characteristic of some of the autosomal dominant craniosynostotic syndromes. Mutations in Crouzon, Jackson-Weiss, Pfeiffer and Apert syndromes have been reported in the FGFR2 extracellular domain. In Crouzon syndrome patients with acanthosis nigricans, a recurrent mutation occurs in the transmembrane domain of FGFR3. We now describe the detection of FGFR2 mutations in the Beare-Stevenson cutis gyrata syndrome. In three sporatic cases, a novel missense mutation was found causing an amino acid to be replaced by a cysteine; two had the identical Ty375Cys mutation in the transmembrane domain and one had a Ser372Cys mutation in the carboxyl-terminal end of the linker region between the immunoglobulin III-like (Iglll) and transmembrane domains. In two patients, neither of these mutations were found suggesting further genetic heterogeneity.

Trichothiodystrophy: clinical spectrum, central nervous system imaging, and biochemical characterization of two siblings.

Trichothiodystrophy (TTD), an autosomal recessive disorder characterized by sulfur-deficient brittle hair, identifies a group of genetic disorders with an altered synthesis of high-sulfur matrix proteins and a defect in excision repair of ultraviolet damage in fibroblasts of most TTD patients. In contrast to patients with xeroderma pigmentosum (XP), TTD patients do not have an increased frequency of skin cancers. TTD patients may be grouped into four categories: 1) those without photosensitivity and without a defect in excision repair of UV damage; 2) those without photosensitivity and with an excision-repair defect in the same gene as in XP-D (complementation group D); 3) those with photosensitivity and with the XP-D repair defect; 4) those with photosensitivity and with a repair defect distinct from that in XP-D. We present a brother and sister in the third category of TTD. Clinically, the patients have brittle hair, short stature, ichthyosis, photosensitivity, nail and dental dysplasias, cataracts, mental retardation, and pyramidal tract abnormalities. Diagnosis was made by hair mount, which shows the characteristic banding pattern with polarizing microscopy, and by hair amino acid analysis, which demonstrated decreased high-sulfur matrix proteins. Fibroblasts cultured from skin biopsies had a marked DNA excision repair defect similar to the repair defect seen in XP-D. We have documented a unique dysmyelinating disorder on magnetic resonance imaging of the brain that might explain their mental retardation, marked hyperactivity, and neurologic deficits. Following the discovery that the human excision repair cross complementing rodent ultraviolet group 2 (ERCC2) gene is able to correct the ultraviolet sensitivity of XP-D cell strains, the ERCC2 cDNA from previous TTD patients was sequenced and shows frameshifts, deletions and point mutations in the ERCC2 gene. Molecular analysis of our patients is in progress. Molecular analysis of the defects in ERCC2 in clinically distinct patients with XP,XP/Cockayne's syndrome, and TTD may provide insight into the molecular mechanisms of these genetically related but clinically distinct disorders.

Emery-Dreifuss muscular dystrophy with autosomal dominant transmission.

A woman with early-onset, slowly progressive, humeroperoneal muscle weakness had marked restriction of neck flexion with contracture at the elbows. She developed exertional dyspnea at age 25, atrial fibrillation with slow ventricular rate was discovered, and a cardiac pacemaker was implanted. Her father had a similar disorder. There is at least one other report of autosomal dominant transmission of this clinical picture, which had previously only been reported as Emery-Dreifuss muscular dystrophy with X-linked recessive inheritance. Thus, more than one mode of inheritance is possible for this unusual and distinctive form of muscular dystrophy.

Hypo-hyperparathyroidism: evidence for a defective parathyroid hormone.

Biochemical evidence for hypoparathyroidism and roentgenographic evidence for hyperparathyroidism were present in a 7-year-old girl with seizures and tetany. She was hypocalcemic (4.7 mg/dl), hyperphosphatemic (11 mg/dl), and normomagnesemic, with elevated parathyroid hormone level (2,603 pg/dl and 3,693 pg/dl in immunoassays utilizing two different antisera). Somatic features of pseudohypoparathyroidism were absent. Increased serum alkaline phosphatase activity (335 IU/liter) with evidence of subperiosteal bone resorption suggested parathyroid hormone activity on bone. Intramuscular administration of parathyroid extract caused a rise in serum calcium level (9.6 mg/dl) and a fall in serum phosphorus level (7.9 mg/dl). The serum calcium, phosphorus, and alkaline phosphatase activity became normal during vitamin D therapy. Parathyroid hormone values and bone roentgenograms became normal. With serum calcium and phosphorus levels normal, ethylenediaminetetraacetic acid infusion was followed by an increase in plasma parathyroid hormone level but not in urinary cyclic adenosine monophosphate (AMP) or phosphaturia; in contrast, parathyroid extract induced cyclic AMP excretion and phosphaturia. These results suggest that endogenous parathyroid hormone in this patient affects bone resorption but not renal handling of phosphate. We infer that this represents a defective endogenous parathyroid hormone.

A new X-linked mental retardation-overgrowth syndrome.

We report on a family with 4 affected males in 3 generations with a previously unreported X-linked mental retardation/multiple congenital anomaly (XLMR/MCA) syndrome. The propositus was a 7-year-old Latin American moderately retarded male with: prenatal and postnatal overgrowth; short, broad upturned nose; large mouth; midline groove of tongue, lower alveolar ridge and lower lip; submucous cleft palate; supernumerary nipples; 13 ribs; Meckel's diverticulum; intestinal malrotation; coccygeal skin tag and bony appendage; hypoplastic index fingernails; postaxial polydactyly of the right hand, bilateral syndactyly of 2nd and 3rd fingers; and tibial clinodactyly of 2nd toes. His sister's son, a premature infant who died at 4 months, had nearly identical manifestations. The propositus and his nephew had normal chromosomes. A brother and son of the sister of the mother of the propositus were similarly affected and both died in the newborn period. The mother of the propositus had a large mouth, coccygeal skin tag and bony appendage, and hypoplastic index fingernails. This distinct mental retardation/multiple congenital anomaly syndrome is added to the growing list of presently known X-linked MCA/MR syndromes.

A new X-linked multiple congenital anomalies/mental retardation syndrome.

We report on 2 boys, the sons of sisters, and their mother's brother who have a new, X-linked multiple congenital anomalies/mental retardation (MCA/MR) syndrome. The propositus was a 16-month-old caucasian male with 1) mental retardation, 2) congenital microcephaly, 3) postnatal growth deficiency, 4) ridged metopic suture with narrow bifrontal diameter, 5) upslanted palpebral fissures with persistent epicanthal folds, strabismus, and lacrimal duct obstruction, 6) narrow palate, 7) macrodontia, 8) anteverted ears, 9) atrial septal defect, 10) dry brittle scalp hair and 11) cutis marmorata. His chromosomes were normal. His cousin and uncle were similarly affected. This distinctive MCA/MR syndrome is added to the list of X-linked malformation syndromes known at the present time.

Alopecia-anosmia-deafness-hypogonadism syndrome revisited: report of a new case.

Johnson et al [1983] reported on a large family with alopecia-anosmia-deafness-hypogonadism syndrome. We report the detailed findings of an unrelated, affected individual and emphasize the presence of hypohidrosis in our case. Our case indicates that this syndrome is not a private syndrome.

Simpson-Golabi-Behmel syndrome: congenital diaphragmatic hernia and radiologic findings in two patients and follow-up of a previously reported case.

This report suggests the association of congenital diaphragmatic hernia in Simpson-Golabi-Behmel syndrome by describing two unrelated males with this malformation. One male was the maternal half-nephew of our previously reported 8-year-old boy with this syndrome. Review of the skeletal roentgenograms of these 2 affected males, and those of the previously reported 8-year-old, documents flare of the iliac wings, narrow sacroiliac notches, and the presence of two carpal ossification centers as a newborn ("advanced bone age"). We also report the follow-up of the 8-year-old boy, now 16 years old, who continues to have significant overgrowth and speech, dental, developmental, and adjustment problems.

Expanded phenotype and ethnicity in Setleis syndrome.

Setleis syndrome, an autosomal recessive disorder characterized by "coarse" face, temporal cutis aplasia, double upper eyelashes, absent lower eyelashes, chronic conjunctivitis, and prominent thick lips, was reported previously in 8 Puerto Rican children. We report on 3 unrelated children (one mentally retarded) with Setleis syndrome who are not of Puerto Rican descent. Two of our patients had imperforate anus, which has not previously been reported. The evolution of the phenotype over time is illustrated.

Pallister-Hall syndrome associated with an unbalanced chromosome translocation.

We report 3 cases of Pallister-Hall syndrome involving hypothalamic hamartoblastoma, hypopituitarism, cranial, and limb abnormalities. The first 2 cases represent the first apparent sibs reported with this syndrome. Patient 1 represents the first known patient with this syndrome with an abnormal karyotype.

Chromosome 22q11.2 microdeletions in velocardiofacial syndrome patients with widely variable manifestations.

Velocardiofacial syndrome (VCFS) and the DiGeorge sequence (DGS) are caused by 22q11.2 deletions. Fluorescence in situ hybridization (FISH) using the DiGeorge chromosome region (DGCR) probe (Oncor) was used to detect 31 deletions in 100 patients with possible VCFS. Retrospective FISH analysis of archived slides from 14 patients originally studied only by high-resolution G banding detected 6 patients with a DGCR deletion, and only 2 of these 6 had a microscopically visible chromosome deletion. The 4 familial deletions found exhibited a wide range of clinical presentations within each family. Comparison of clinical characteristics of patients with and without the DGCR deletion determined findings predictive of the deletion: abundant or unruly scalp hair; narrow palpebral fissures; a laterally "built-up" nose; velopharyngeal inadequacy; thymic hypoplasia; and congenital heart defects, specifically tetralogy of Fallot, ventriculoseptal defect, and interrupted aortic arch.

Cardio-facio-cutaneous syndrome phenotype in an individual with an interstitial deletion of 12q: identification of a candidate region for CFC syndrome.

We report on a 19-month-old girl who presented with the phenotype of cardio-faciocutaneous (CFC) syndrome including characteristic minor facial anomalies, cardiac defect, ectodermal anomalies, and developmental delay. Cytogenetic analysis showed the presence of an interstitial deletion of one chromosome 12, del(12)(q21.2q22), confirmed by fluorescence in situ hybridization with chromosome band specific probes. Controversy exists as to whether CFC and Noonan syndrome (NS) are distinct disorders, a contiguous gene syndrome, or allelic variants. The identification of the del(12) in this patient, in a region distinct from the putative NS locus, supports the view that CFC is a genetically distinct condition from NS. In addition, this implicates the region 12q21.2-->4q22 as a candidate region for the gene(s) causing CFC syndrome.

Beare-Stevenson cutis gyrata syndrome.

Beare-Stevenson cutis gyrata syndrome consists of skin furrows of corrugated appearance, acanthosis nigricans, craniofacial anomalies, particularly craniosynostosis and ear defects, anogenital anomalies, skin tags, and prominent umbilical stump. Four cases of this striking syndrome are reported. Together with two previously reported cases, the syndrome is delineated from the six known cases. Cutis gyrata variably affects the scalp, forehead, face, preauricular area, neck, trunk, hands, and feet. Craniosynostosis is present in four cases, with cloverleaf skull in three of these. Intrauterine growth has been normal in all cases. Performance and life expectation appear to be related to the presence or absence of cloverleaf skull. All cases observed to date have been sporadic. Increased paternal age suggests the possibility of an autosomal dominant mutation.

Severe congenital anomalies requiring transplantation in children with Kabuki syndrome.

Kabuki syndrome (KS) is a rare multiple malformation disorder characterized by developmental delay, distinct facial anomalies, congenital heart defects, limb and skeletal anomalies, and short stature. Renal anomalies have been reported in a few cases of KS, but to our knowledge, hepatic anomalies have not. Here, we document two cases of KS requiring liver or kidney transplantation: one with severe hepatic and renal anomalies and one with severe renal anomalies. Both cases had the characteristic facial appearance of children with KS, postnatal growth deficiency, and developmental delay. At birth, case 1 presented with hypoglycemia, ileal perforation, right hydroureter, and hydronephrosis. The patient subsequently developed hyperbilirubinemia, hepatic abscess, and cholangitis. At age 8 months, he underwent a liver transplant. Hepatic pathology diagnosed neonatal sclerosing cholangitis. Case 2 presented with renal failure at age 6 years. Renal ultrasound study showed markedly dysplastic kidneys requiring transplantation. In addition to characteristic findings of KS, she had coronal synostosis and was shown to have immune deficiency and an autoimmune disorder manifesting as Hashimoto thyroiditis and vitiligo. We conclude: 1) severe hepatic and renal anomalies leading to organ failure can occur in KS; 2) patients with neonatal sclerosing cholangitis should be examined closely for features of KS; 3) coronal synostosis may occur in KS; and 4) immune deficiency and autoimmune disorder can be associated with KS.

Smith-Lemli-Opitz syndrome-type II: multiple congenital anomalies with male pseudohermaphroditism and frequent early lethality.

In 1964, Smith et al described a syndrome of microcephaly, growth and mental retardation, unusual facial appearance, syndactyly of toes 2 and 3, and genital abnormalities. Major structural malformations and early death have been uncommon in the many subsequent literature reports. We report on 19 infants with a phenotype we propose to call Smith-Lemli-Opitz syndrome (SLOS)-Type II, in which major structural abnormalities, male pseudohermaphroditism, and early lethality are common. Of these 19 patients, 18 had postaxial hexadactyly, 16 had congenital heart defect, 13 had cleft palate, and 10 had cataracts. Unusual findings seen in these patients at autopsy included Hirschsprung "disease" in five patients, unilobated lungs in six, large adrenals in four, and pancreatic islet cell hyperplasia in three. Comparison of our cases to 19 similar literature cases suggests the existence of a distinct phenotype that may be separate from SLOS as originally described. It is also inherited as an autosomal recessive, as documented by occurrence in one pair of sibs in this study and recurrence in three reported families.

Mental retardation locus in Xp21 chromosome microdeletion.

Xp21 microdeletion syndrome is associated with variable size Xp21 deletions that usually include the glycerol kinase locus. The clinical phenotypes we studied in this chromosome region include: Xpter - Aland Island eye disease (AIED) -adrenal hypoplasia (AH) -glycerol kinase (GKD) -Duchenne muscular dystrophy (DMD) -retinitis pigmentosa (RP) -ornithine transcarbamylase (OTC) -centromere. In a compilation of 18 individuals in 14 families with the AH, GKD, and DMD loci deleted, 17 were male and all were developmentally delayed. In contrast, we report mentally retarded female carriers in two Xp21 deletion syndrome families with DMD, GKD, and AH in affected males. In the first family with normal karyotypes, a submicroscopic deletion was associated with DMD in the retarded male and with retardation in carrier females. In the second family an X chromosome with a cytogenetically deleted Xp21 distal to the OTC and RP genes segregated in the affected male and retarded female carriers. DNA analysis at the DMD locus verified the cytogenetic findings. This report of mental retardation in otherwise asymptomatic female carriers of Xp21 deletion classifies one form of mental retardation in females.

Oculoauriculovertebral abnormalities in children of diabetic mothers.

Maternal diabetes is known to have teratogenic effects. Malformations including neural tube defects, caudal dysgenesis, vertebral defects, congenital heart defects, femoral hypoplasia, and renal anomalies are described in infants of diabetic mothers. However, craniofacial anomalies have rarely been reported in such infants. Here we document craniofacial anomalies of patients born to diabetic mothers. We describe two patient populations: individuals evaluated through our genetics services for multiple malformations and individuals identified through a database search in our craniofacial clinic. The first group consists of 14 individuals evaluated in our genetics clinics who were born to diabetic mothers and had craniofacial anomalies. The second group consists of seven individuals who were identified from a craniofacial database search of patients with hemifacial microsomia and who were born to diabetic mothers. Thus, both groups were born to diabetic mothers and had hemifacial microsomia (67%), microtia (52%), hearing loss (43%), epibulbar dermoids (24%), and fused cervical vertebrae (24%). Therefore, the teratogenic effects of maternal diabetes probably include such craniofacial malformations as the oculoauriculovertebral/Goldenhar complex. Infants of diabetic mothers should be evaluated for craniofacial anomalies. Conversely, mothers of infants with craniofacial anomalies should be evaluated for diabetes to aid in counseling concerning cause and recurrence risks.

True trisomy 2 mosaicism in amniocytes and newborn liver associated with multiple system abnormalities.

Among 58,000 amniocenteses completed, our laboratories found one case of true cytogenetic trisomy 2 mosaicism in a fetus with multiple abnormalities. In contrast, 11 fetuses phenotypically normal at birth were found to have true trisomy 2 mosaicism in their chorionic villus cells among the 10,500 fetuses tested by chorionic villus sampling (CVS). In our single abnormal case, amniocentesis performed at 19 weeks after finding an elevated maternal serum AFP found two independent cultures with trisomy 2 karyotypes in 8 of 25 and 7 of 31 amniocytes, respectively. Although oligohydramnios was noted by ultrasound, the mother elected to continue the pregnancy. At 26 weeks the fetus had intrauterine growth retardation (IUGR), hydronephrosis, and cardiac abnormalities. When delivered by Cesarean section at 30 weeks, the infant had multiple anomalies and developed necrotizing enterocolitis and severe cholestasis. At 5 months coronal magnetic resonance imaging (MRI) displayed delayed myelination and abnormal brain morphology. The patient also exhibited significant growth failure and developmental delay. Although chromosomes were normal in blood, skin fibroblasts, and ascites fluid cells, 4 of 100 hepatic biopsy fibroblasts were 47,XY,+2. Molecular analysis excluded uniparental disomy (UPD) of chromosome 2 in the 46,XY cell line. This and other reports of rare phenotypically abnormal trisomy 2 mosaic fetuses identified by karyotyping amniocytes emphasizes the substantially higher fetal risk of abnormal development than when trisomy 2 is found only in chorionic villus cells.

Apparent cyclophosphamide (cytoxan) embryopathy: a distinct phenotype?

Cyclophosphamide (CP) is an alkylating agent widely used in treating cancer and autoimmune disease. CP is classified as a pregnancy risk factor D drug and is teratogenic in animals, but population studies have not conclusively demonstrated teratogenicity in humans. Six isolated reports of prenatally exposed infants with various congenital anomalies exist, but to date no specific phenotype has been delineated. The purpose of this report is to document a new case of in utero CP exposure with multiple congenital anomalies and to establish an apparent CP embryopathy phenotype. The mother had systemic lupus erythematosus and cyclophosphamide exposure in the first trimester. She also took nifedipine, atenolol, clonidine, prednisone, aspirin, and potassium chloride throughout pregnancy. The infant had growth retardation and multiple anomalies including microbrachycephaly, coronal craniosynostosis, hypotelorism, shallow orbits, proptosis, blepharophimosis, small, abnormal ears, unilateral preauricular pit, broad, flat nasal bridge, microstomia, high-arched palate, micrognathia, preaxial upper limb and postaxial lower limb defects consisting of hypoplastic thumbs, and bilateral absence of the 4th and 5th toes. Chromosomes were apparently normal. The reported cases of in utero exposure to cyclosposphamide shared the following manifestations with our patient: growth deficiency, developmental delay, craniosynostosis, blepharophimosis, flat nasal bridge, abnormal ears, and distal limb defects including hypoplastic thumbs and oligodactyly. We conclude that (a) cyclophosphamide is a human teratogen, (b) a distinct phenotype exists, and (c) the safety of CP in pregnancy is in serious question.

Congenital diaphragmatic defects and associated syndromes, malformations, and chromosome anomalies: a retrospective study of 60 patients and literature review.

Congenital diaphragmatic defects (CDDs) may occur in malformation syndromes of varied causes. Syndromic cases of CDDs due to chromosomal defects, autosomal recessive, autosomal dominant, or X-linked inheritance have been described. In order to determine the frequency and nature of syndromes, malformations, and chromosome abnormalities associated with CDDs, we reviewed the records of all patients with CDDs evaluated over a 4-year period. During the 4-year interval, a total of 60 patients was evaluated. Of these, 29 had a therapeutic or spontaneous abortion, and 31 received postnatal care. On prenatal ultrasonography, 20 of 60 (33%) of patients with CDDs had additional anomalies. Additional anomalies, besides CDDs, were present in 15 of 31 (48%) of liveborn patients on newborn evaluation. In total, 16 patients with multiple anomalies were evaluated. Of these, 12 of 16 (75%) had additional abnormalities detected by prenatal ultrasonography. The 4 of 16 (25%) without additional anomalies on prenatal sonography had multiple anomalies found neonatally, lethal multiple pterygium syndrome being diagnosed in one case. Prenatal chromosome analysis was performed in 7 of 16 patients, and all had postnatal karyotypes. All initial karyotypes were normal. Tetrasomy 12p was documented on postnatal fibroblast analysis in one case who had percutaneous umbilical blood sampling (PUBS). Syndromes diagnosed postnatally in 7 of 16 patients (44%) include: Fryns syndrome (2), Simpson-Golabi-Behmel syndrome (2), tetrasomy 12p (1), Brachmann-de Lange syndrome (1), and lethal multiple pterygium syndrome (1). We were unable to make a specific diagnosis in 9 of 16 patients (56%) with multiple malformations. In patients with CDDs, a normal prenatal karyotype, especially if obtained by PUBS, and absence of other detected abnormalities by fetal ultrasonography, do not exclude the presence of other major anomalies, including chromosome abnormalities and severe multiple malformation syndromes.