Adults with Sotos syndrome: review of 21 adults with molecularly confirmed NSD1 alterations, including a detailed case report of the oldest person.

Sotos syndrome is a well-described multiple anomaly syndrome characterized by overgrowth, distinctive craniofacial appearance, and variable learning disabilities. The diagnosis of Sotos syndrome relied solely on these clinical criteria until haploinsufficiency of the NSD1 gene was identified as causative. We describe a 63-year-old woman with classic features and a pathogenic NSD1 mutation, who we believe to be the oldest reported person with Sotos syndrome. She is notable for the diagnosis of Sotos syndrome late in life, mild cognitive limitation, and chronic kidney disease attributed to fibromuscular dysplasia for which she recently received a transplant. She has basal cell and squamous cell carcinoma for which her lifetime of sun exposure and fair cutaneous phototype are viewed as risk factors. We also reviewed previous literature reports (n = 11) for adults with Sotos syndrome, and studied patients ascertained in the Spanish Overgrowth Syndrome Registry (n = 15). Analysis was limited to 21/27 (78%) total patients who had molecular confirmation of Sotos syndrome (15 with a mutation, 6 with a microdeletion). With a mean age of 26 years, the most common features were learning disabilities (90%), scoliosis (52%), eye problems (43%), psychiatric issues (30%), and brain imaging anomalies (28%). Learning disabilities were more severe in patients with a microdeletion than in those with a point mutation. From this small study with heterogeneous ascertainment we suggest modest adjustments to the general healthcare monitoring of individuals with Sotos syndrome. Although this series includes neoplasia in four cases, this should not be interpreted as incidence. Age-appropriate cancer surveillance should be maintained.

In-frame deletion in FLNA causing familial periventricular heterotopia with skeletal dysplasia in males.

Periventricular heterotopia (PH) is an etiologically heterogeneous disorder characterized by nodules of neurons ectopically placed along the lateral ventricles. Truncating and missense mutations of the FLNA gene have been identified in almost 100% of families and 26% of sporadic patients with PH. The otopalatodigital syndrome spectrum is caused by distinct FLNA missense mutations or in-frame deletions disrupting the development of craniofacial and long bones. We report on a clinical, neuroimaging, X-ray, and molecular study of a family in which classical bilateral PH appeared as an isolated anatomic feature in the mother and was associated with skeletal abnormalities and facial dysmorphisms in her two sons. Both boys exhibited PH associated with flat face and spatulate finger tips, short broad phalanx and metacarpus, and bowed radius with dislocated wrist joints. All three patients harbored the c.7865_7870del in-frame deletion (p.2622_2623delDK) in the carboxyl-terminal domain (repeat 24) of FLNA. The X-inactivation observed in the mother was skewed towards the mutant allele, resulting in the preferential expression of the wild-type allele. The in-frame deletion in the carboxyl-terminal domain of FLNA caused a phenotype in which PH was associated with skeletal features suggestive of the otopalatodigital syndrome spectrum in boys. There appears to be a continuum among allelic disorders due to FLNA mutations.

Screening for subtelomeric chromosome alteration in a consecutive series of newborns with congenital defects.

It is generally accepted that 2.5% of the patients with unexplained mental retardation and dysmorphic features have a chromosome alteration affecting the subtelomeric regions. The frequency of such alterations whether in the general population or in newborns with congenital defects, however, remains unknown. Here, we present an analysis of the subtelomeric regions in a consecutive series of 71 newborn babies with congenital defects, who displayed a normal high resolution G-band karyotype (550-850 bands). After excluding the alterations that could be considered to be polymorphisms, a total of seven subtelomeric anomalies were observed with a frequency of 9.86% (3.96-20.31). We conclude that fluorescence in-situ hybridization screening for subtelomeric alterations is relevant for infants with congenital defects detectable at birth, particularly in those newborn babies with congenital defects and a normal high resolution G-band karyotype.

Comprehensive screening of CREB-binding protein gene mutations among patients with Rubinstein-Taybi syndrome using denaturing high-performance liquid chromatography.

Mutations in the CREBBP (CREB-binding protein gene) cause Rubinstein-Taybi syndrome (RSTS). At present, however, genetic testing of CREBBP is not commonly applied in clinical settings because the currently available assays are technically and financially demanding, mainly because of the size of the gene. In the present study, we took advantage of a highly sensitive and specific, automated denaturing high-performance liquid chromatography (DHPLC) technique. First, we developed a DHPLC-based protocol to analyze the entire coding region of CREBBP. Second, we analyzed genetic samples from 21 RSTS patients using DHPLC. The coding region was amplified by 41 primer pairs, all of which have the same cycling conditions, aliquoted on a 96-well format PCR plate. In this manner, all the exons were simultaneously amplified using a single block in a PCR machine. We then wrote a computer script to analyze all the PCR amplicons generated from various portions of the CREBBP gene in a serial manner at optimized conditions determined individually for each amplicon. Heterozygous CREBBP mutations were identified in 12 of the 21 patients: five frameshift mutations, three nonsense mutations, two splice-site mutations, and two missense mutations. The resulting detection rate of 57% was comparable to the outcome of previous studies. The relatively high detection rate in the present study demonstrates the enhanced sensitivity of the DHPLC-based mutation analysis, as exemplified by mutation analyses of other genes. The implementation of similar methodologies for other dysmorphic syndromes will help medical geneticists to confirm their clinical impressions and to provide accurate genetic counseling for patients and their families.

High resolution microarray CGH and MLPA analysis for improved genotype/phenotype evaluation of two childhood genetic disorder cases: ring chromosome 19 and partial duplication 2q.

A detailed analysis of the constitutional chromosomal changes in two pediatric patients was performed using high resolution genetic analysis techniques, microarray comparative genomic hybridization (array CGH) and multiplex ligation-dependent probe amplification (MLPA) as well as FISH. The aim was to come to a more precise characterization of the genotype/phenotype relationship. Case 1 was a girl of 25 months, showing areas of hypopigmentation along the lines of Blaschko and no other developmental abnormality. She carried a ring chromosome 19 which we found not to have resulted in loss of subtelomeric sequences, ruling out the possibility that a small subtelomeric loss was causally related to this patient's phenotype. Case 2 was a 9-year-old girl with facial anomalies and mild growth and mental retardation carrying an unidentified addition on chromosome 2p. We found that the addition was duplicated 2q35-q37.3 and that the addition was not accompanied by loss of 2pter or any other chromosomal region. Together with literature data, we hypothesize that pediatric patients with 'pure' trisomy 2q including bands 2q35-q37.1 may have a moderate clinical phenotype as opposed to patients with duplications proximal to 2q33 or patients with duplications 2q3 with accompanying distal deletion. These two examples illustrate the additional value of new, high resolution genetic analysis techniques for a better characterization of the genotype/phenotype relationship in childhood chromosomal disorders.

Growth deficiency, facial anomalies, and brachydactyly (Frías syndrome): a second family.

A second family with the condition first described by Frías et al. in 1975 is presented. Those authors examined a mother and her son affected with short stature, facial anomalies (epicanthic folds, downward palpebral fissures, hyperthelorism, and eyelid ptosis), cup-shaped and posteriorly rotated ears, hand and foot defects, and delayed bone age. In the family we are presenting here, a girl, her mother, the mother's brother, and the propositus' maternal grandmother, were affected. This supports autosomal dominant inheritance, as proposed by (Frías et al. [1975] BDOAS 11:30-33), although with variable expressivity.