SOS1 is the second most common Noonan gene but plays no major role in cardio-facio-cutaneous syndrome

Background

Heterozygous gain‐of‐function mutations in various genes encoding proteins of the Ras‐MAPK signalling cascade have been identified as the genetic basis of Noonan syndrome (NS) and cardio‐facio‐cutaneous syndrome (CFCS). Mutations of SOS1, the gene encoding a guanine nucleotide exchange factor for Ras, have been the most recent discoveries in patients with NS, but this gene has not been studied in patients with CFCS.

Methods and results

We investigated SOS1 in a large cohort of patients with disorders of the NS–CFCS spectrum, who had previously tested negative for mutations in PTPN11, KRAS, BRAF, MEK1 and MEK2. Missense mutations of SOS1 were discovered in 28% of patients with NS. In contrast, none of the patients classified as having CFCS was found to carry a pathogenic sequence change in this gene.

Conclusion

We have confirmed SOS1 as the second major gene for NS. Patients carrying mutations in this gene have a distinctive phenotype with frequent ectodermal anomalies such as keratosis pilaris and curly hair. However, the clinical picture associated with SOS1 mutations is different from that of CFCS. These findings corroborate that, despite being caused by gain‐of‐function mutations in molecules belonging to the same pathway, NS and CFCS scarcely overlap genotypically.     

Meier‐Gorlin syndrome (ear–patella–short stature syndrome) in an Italian patient: Clinical evaluation and analysis of possible candidate genes

Florescence in situ hybridization (FISH) using subtelomeric probes has been useful in detecting cryptic telomeric chromosomal rearrangements. We report, for the first time, that cytogenetically visible chromosome rearrangements can occur between the subtelomeric and telomeric region in clinically normal individuals with balanced chromosome anomalies in which one of the breakpoints involves a terminal band region. Using FISH with subtelomeric probes, we observed in three cases with a balanced reciprocal translocations the retention and subsequent loss of subtelomeric regions. In one case with a paracentric inversion, there was a proximal relocation of a subtelomeric region. Because subtelomeric regions serve important roles in chromosome pairing, this retention and concomitant loss or relocation of a subtelomeric region could possibly further disrupt the complex meiotic configurations of these balanced chromosome rearrangements. This may then have an effect on gamete production, placing these individuals at a higher risk for miscarriages and/or abnormal outcomes for individuals with similar chromosome aberrations. © 2002 Wiley‐Liss, Inc.     

New syndrome of macrocephaly,hypertelorism, short limbs,hearing loss,and developmental delay

We describe a boy with an apparently unique constellation of anomalies, including macrocephaly, short stature, relatively short limbs, hearing loss, developmental delay, sparse anterior scalp hair, hypertelorism, downslanting palpebral fissures, and a short nose with a broad, flat nasal bridge and anteverted nares. Chromosomes were normal and radiographs failed to show a bone dysplasia. We conclude that this represents a new syndrome. © 1995 Wiley-Liss, Inc.     

Provisionally unique autosomal recessive chondrodysplasia punctata syndrome

Stippled epiphyses occur in several monogenie, teratogenic, or aneuploidy syndromes. We describe two sibs with a provisionally unique chondrodysplasia punctata syndrome, who have, in addition to stippled epiphyses, minor facial anomalies, short stature, and ocular colobomata. Inheritance of this condition is likely autosomal recessive. © 1993 Wiley-Liss, Inc.     

A dominantly inherited malformation syndrome with short stature,upper limb anomaly,minor craniofacial anomalies,and absence of TBX5 mutations: Report of a Thai family

We report on a Thai family with dominantly inherited malformation syndrome with upper limb anomalies, short stature, quadricuspid aortic valve, and minor craniofacial anomalies. The affected individuals comprised a mildly affected mother, a moderately affected daughter, and a most severely affected son. The daughter and son had short stature. The craniofacial abnormalities comprised frontal bossing, hypoplastic nasal bones, depressed nasal bridge, and broad nasal alae. The upper limb defects varies among the patients, ranging from radial ray defects in the mother through radial and ulnar ray defects with unilateral humeral hypoplasia in the daughter to radial ray defects with severe oligodactyly and bilateral humeral hypoplasia in the son. All patients in this family had hypoplasia of the shoulder girdle and resembled what is observed in many families with Holt‐Oram syndrome. Moreover, the son showed quadricuspid aortic valve with mild aortic regurgitation. However, the present family did not show any mutation of the TBX5 gene, a disease‐causing gene of Holt‐Oram syndrome. The present family deserves further investigation on other genes that play a role in the development of the upper limbs, particularly of radial rays. © 2002 Wiley‐Liss, Inc.     

Microcephaly-lymphedema syndrome: Report of a family with short stature as additional manifestation

Patients with the rare autosomal dominant microcephaly-lymphedema syndrome have apparently normal intelligence. We report on a boy with microcephaly, lymphedema, and short stature as an additional manifestation. The family history of our patient suggests autosomal dominant inheritance with reduced penetrance and variable expressivity. However, X-linked inheritance cannot be excluded. Am. J. Med. Genet. 80:506–509, 1998. © 1998 Wiley-Liss, Inc.     

Growth manifestations in the Brachmann-de Lange syndrome

We have obtained serial measurements on 180 patients with clinically confirmed Brachmann-de Lange syndrome (BDLS) in order to derive standard growth curves. The patients were evaluated in our genetics department and through meetings of the Cornelia de Lange Syndrome Foundation, a support group for families of affected individuals. The data were obtained from the records of pediatricians, other physicians, schools and parents, as well as from personal examination on each of these patients at least once, often periodically. The growth curves include height, weight and head circumference measurements from birth through adulthood. Prenatal growth and birth weights are below the 5th centile in most (68%) cases, with an average birth weight of 2,277 g. Growth persists below the normal curves in most of the patients throughout life. Height velocity is equal to the normal range but there is slower pubertal growth. Weight velocity is below the normal range throughout life until late adolescence. Average head circumference remains below the second centile. Thin body habitus coupled with slow growth and proportionate small stature is a manifestation of the syndrome, but is commonly mistaken for failure to thrive. © 1993 Wiley-Liss, Inc.     

Steinfeld syndrome: Report of a second family and further delineation of a rare autosomal dominant disorder

We report on a fetus with alobar holoprosencephaly, microphthalmia, midline cleft lip and palate, absent nose, dysplastic ears, radial defects, pentalogy of Fallot, unilateral renal aplasia, absent gallbladder, vertebral anomalies, and absence of ribs. The father had a cleft palate, bilateral colobomas of the iris and retina, a bifid uvula, vertebral anomalies, and unilateral congential hearing loss. His sister had a cleft lip. On the basis of this family and the family reported by Steinfeld [1982], this malformation syndrome can be defined as a rare autosomal dominant syndrome whose main component manifestations are holoprosencephaly, predominantly radial limb deficiency, heart defects, kidney malformations, absence of gallbladder, and vertebral anomalies. © 1993 Wiley-Liss, Inc.     

Isochromosome Xq in Klinefelter syndrome: Report of 7 new cases

In this collaborative study we report on 2 prenatally and 5 postnatally diagnosed cases with a 47,X,i(Xq), Y chromosomal constitution. Excepting tall stature, the 5 adult patients showed all typical manifestations of Klinefelter syndrome. Taken together with previously reported cases, these data suggest that Klinefelter syndrome with isochromosome Xq has a favorable prognosis with normal mental development, and with normal-to-short stature. The prevalence of this Klinefelter variant is calculated to be between 0.3–0.9% in males with X chromosome polysomies. © 1996 Wiley-Liss, Inc.     

Juberg-Marsidi syndrome: Report of an additional case

We report on a 2-year-old boy with Juberg-Marsidi syndrome. He has mental retardation, short stature, micropenis, cryptorchidism, and minor facial abnormalities. His Leidig cells responded to the administration of human chorionic gonadotropin and there were positive responses of LH and FSH to the administration of LH-RH. He showed normal weight gain and head circumference which have not been described previously. The association of Juberg-Marsidi syndrome with HbH disease was ruled out in the propositus. © 1995 Wiley-Liss, Inc.     

Short stature in a patient with Klinefelter syndrome and growth hormone deficiency

We report on a child with Klinefelter syndrome and short stature due to idiopathic growth hormone deficiency (IGHD). His height was below the mid-parental height, with a significant delay in bone age. Height velocity increased from 4.5 to 8.2 cm/year during 1 year of GH therapy and typical catch-up growth was observed. No adverse reactions to the treatment were observed. We wish to emphasize the rare association between Klinefelter syndrome and IGHD and the apparent effectiveness and safety of recombinant somatotropin treatment in aneuploid patients. © 1994 Wiley-Liss, Inc.     

Extending the spectrum of distal arthrogryposis

We describe a mother and son with multiple, non-progressive, congenital contractures, camptodactyly and absent flexion creases, expressionless face, blepharophimosis, microstomia, and short stature. Although these cases share similarities with the autosomal-recessive Schwartz-Jampel and Marden-Walker syndromes, they have a different mode of inheritance and lack myotonia, one of the most characteristic findings of the Schwartz-Jampel syndrome. Our cases most closely resemble those previously reported as distal arthrogryposis type IIb, although in our patients the proximal joints are severely affected and extraocular involvement is absent. Hearing loss is present in one and cleft palate in the other of our patients; these findings were previously described in arthrogryposis syndromes other than type IIb. We suggest extending the spectrum of distal arthrogryposis to include these manifestations, since there appears to be significant overlap between the different syndromes. © 1996 Wiley-Liss, Inc.     

Oto-facio-osseous-gonadal syndrome: a new form of syndromic deafness?

In this study, we report on two brothers, born to consanguineous parents, with a syndrome of sensorineural deafness, short stature, cryptorchidism, inguinal hernia, brachycephaly, prominent forehead, flat face, downslanting palpebral fissures, low nasal root, hypoplastic alae and round tip to the nose, low-set prominent ears, narrow thorax, genu valgum, wormian bones, fusion of carpal bones, delayed bone age and congenital clubfeet. This combination of anomalies appears to be a previously undescribed syndrome, with probable autosomal recessive inheritance.     

Another postnatal-onset obesity syndrome

We describe an apparently newly recognized postnatal-onset obesity syndrome with short stature, mental deficiency, hypogonadism, micropenis, contractures of the fingers, and cleft lip-palate. Comparison is made with other postnatal-onset obesity syndromes, particularly Vasquez syndrome and Urban syndrome. The cause of our patient's syndrome is unknown at present. We encourage the reporting of other cases to help clarify whether our patient represents a separate entity. © 1993 Wiley-Liss, Inc.     

Physical growth in Brachmann-de Lange syndrome

Growth in 30 patients with Brachmann-de Lange syndrome (BDLS) was evaluated and found to be deficient in 27/30, with 17/27 having intrauterine growth retardation (IUGR). In 12/27 Patients, endocrine evaluations have been completed. Seven of 12 were normal and 4/12, one with empty sella, had “classical” growth hormone deficiency with extreme short stature, markedly delayed skeletal maturation and subnormal growth hormone secretion in response to provocative stimuli. One of 12 patients had discordance between insulin growth factor I levels and growth hormone responses to insulin and clonidine suggestive of end organ resistance to growth harmone. It appears that the hypothalmamic-pituitary function is compromised in at least some BDLS patients. Thus, endocrine evaluations are warranted for the patients with short stature. © 1993 Wiley-Liss, Inc.     

Early recognition of the Coffin-Lowry syndrome

We report a 2-year-old male infant with the Coffin-Lowry syndrome, and describe the change in his clinical and radiographic manifestations during the first 2 years of life. Review of published cases of the Coffin-Lowry syndrome indicates that these manifestations are progressive, and that all of the associated characteristics may not be apparent in early childhood. The importance of continued evaluations of these patients and examination of relatives for mild manifestations is emphasized.     

Familial transmission of a duplication-deficiency X chromosome associated with partial Turner syndrome

A rearranged X chromosome Xqter→q13::Xp11.4→qter was found in a mother and her two daughters, who were affected with short stature, cubitus valgus and hypothyroidism. The mother's menstrual cycles were normal until the age of premenopause. Similar previously reported cases are considered in an attempt to explain the possible origin of this X recombinant, fertility and clinical traits.