Fraternal twins with Aarskog-Scott syndrome due to maternal germline mosaicism.

Aarskog-Scott syndrome is a rare X-linked recessive disorder with characteristic facial, skeletal, and genital abnormalities. We report on Aarskog-Scott syndrome in male dizygotic twins with an identical de novo mutation in FGD1 that resulted from germline mosaicism in the phenotypically normal mother. This is the first report of inheritance by germline mosaicism for the FGD1 gene.

Delayed puberty due to a novel mutation in CHD7 causing CHARGE syndrome.

We report the case of a 15-year-old girl who presented to a pediatric endocrinology clinic for delayed puberty with no signs of secondary sexual development. Her past medical history was significant for bilateral colobomas, inner-ear anomalies, hearing loss, and anosmia. Genetic testing revealed a novel de novo mutation in the CHD7 gene, one of the causative genes in CHARGE syndrome (coloboma, heart disease, choanal atresia, retarded growth and development and/or central nervous system anomalies, genital anomalies and/or hypogonadism, and ear anomalies and/or deafness). We review the distinction between hypogonadotrophic hypogonadism and hypergonadotrophic hypogonadism and discuss the availability of molecular genetic testing for idiopathic hypogonadotrophic hypogonadism. CHD7 mutations have also been found in some patients with Kallmann syndrome, hypogonadotrophic hypogonadism, and anosmia, and we discuss the overlap between this syndrome and CHARGE syndrome. With the increased availability of genetic testing for a variety of disorders, it is important for pediatricians to become familiar with interpreting genetic test results. Finally, we illustrate that Bayes' theorem is a useful statistical tool for interpreting novel missense mutations of unknown significance.

Prenatal molecular diagnosis of tuberous sclerosis complex.

OBJECTIVE: The objective of the study was to report experience with prenatal molecular diagnosis of tuberous sclerosis complex (TSC). STUDY DESIGN: Sequential deoxyribonucleic acid (DNA) studies were performed on amniotic fluid cells and chorionic villi from 50 pregnant women at risk for having a child with TSC. Mutations were determined by gene sequencing and deletion/duplication analysis of the 2 TSC genes. RESULTS: DNA analysis was successful in 48 of 50 tested fetuses. Mutations were precisely identified in a family member (24) (TSC1 [5]; TSC2 [19]) and/or fetus (11) (TSC1 [3]; TSC2 [8]). Novel mutations were found in 19 individual families, and a probable polymorphism was noted in 4. Second-trimester ultrasound detected 18 fetuses with cardiac rhabdomyomas. There was insufficient DNA in 1, whereas 8 of 17 (47%) had a mutation, 6 (75%) being in TSC2. In 4 of 18 cases, a mutation was detected in the fetus for the first time despite a parent known to have TSC. CONCLUSION: The value and utility of prenatal diagnosis of TSC by DNA analysis was demonstrated by the results in this series of 50 pregnancies in women at risk of having affected offspring. A family history of TSC or detection of fetal cardiac rhabdomyoma should prompt genetic evaluation and counseling of parents and the option of prenatal diagnosis.

A 21 years follow-up of a girl patient with a pseudodicentric bisatellited chromosome 22 associated with partial trisomy 22pter-->22q12.1: clinical, cytogenetic and molecular observations.

We present clinical and developmental data on a patient with a de novo recombinant pseudodicentric bisatellited chromosome 22 associated with a partial trisomy 22pter-22q12.1. The patient was evaluated at birth and followed-up until 21 years of age. Clinical findings include facial and digital dysmorphism, hydrocephalus and postnatal-onset growth deficiency. The patient showed bilateral microphthalmia with severe palpebral ptosis and coloboma of the iris and left optic nerve. She also has skeletal and neurological abnormalities, cholesteatoma and seizures. She had absence of speech, poor mobility, poor vision and required help with all daily living skills. Conventional chromosome GTG banded analysis showed that the proband had an abnormal karyotype:46,XX,add(22)(q13). Fluorescence in situ hybridization (FISH) analyses and microsatellite markers for DNA polymorphism study ascertained the karyotype as 46,XX,add(22)(q13.3).ish psu dic(22;22)(q13.3;q12.1)(D14Z1/D22Z1++, N25++, ARSA+, PCP22q+). The recombinant chromosome was stable and present in all cells examined. The paternal origin of the psu dic(22;22) chromosome was determined by using five highly polymorphic microsatellite markers located to the region of chromosome 22q11.2-22q13.33. A 22q13.3 monosomy was ruled out with 22q13.3 cosmid probes covering the terminal 22q-140Kb. The proband carried a recombinant pseudodicentric bisatellited chromosome psu dic(22;22)(q13.3;q12.1). To our knowledge, this is the first report of such rearrangement resulting in partial trisomy 22pter-22q12.1.

Molecular, biochemical, and phenotypic analysis of a hemizygous male with a severe atypical phenotype for X-linked dominant Conradi-Hunermann-Happle syndrome and a mutation in EBP.

X-linked dominant Conradi-Hunermann-Happle syndrome (CDPX2; MIM 302960) is a rare chondrodysplasia punctata primarily affecting females. CDPX2 is presumed lethal in males, although a few affected males have been reported. CDPX2 is a cholesterol biosynthetic disorder due to 3-beta-hydroxysteroid-delta8,delta7-isomerase deficiency caused by mutations in the emopamil binding protein (EBP) gene. A 2.5-year-old Caucasian male was followed from the age of 6 weeks and noted to have significant developmental delay, hypotonia, seizures, and patchy hypopigmentation. Multiple congenital anomalies included a unilateral cataract, esotropia, crossed renal ectopia, stenotic ear canals, and failure to thrive, requiring G-tube placement. Multiple minor anomalies and ptosis were noted. No skeletal asymmetry or chondrodysplasia punctata were noted on skeletal survey at 6 weeks and 13 months. An extensive genetic work-up including cholesterol (126-176 mg/dl) and 7-dehydrocholesterol was unrevealing. However, the levels of 8(9)-cholestenol and 8-dehydrocholesterol were mildly increased in plasma, which was confirmed in cultured fibroblasts. This prompted molecular analysis of the EBP gene, which revealed a novel hemizygous (nonmosaic) mutation in exon 2 (L18P). Two restriction digests were developed that confirmed this mutation in skin fibroblasts, blood, and buccal cells (all nonmosaic). We determined that the patient's mother (adopted) also has the L18P mutation enabling prenatal diagnosis of a normal male fetus. She has normal stature, no asymmetry, no cataracts at this time, and has a patch of hyperpigmentation on her chest best visualized on Woods lamp examination, characteristic of CDPX2. The mild maternal phenotype has been described previously. However, this nonmosaic missense mutation has resulted in a severe phenotype in her surviving son.