ADA2 deficiency in a patient with Noonan syndrome‐like disorder with loose anagen hair: The co‐occurrence of two rare syndromes

Noonan syndrome‐like disorder with loose anagen hair (NS/LAH) is one of the RASopathies, a group of clinically related developmental disorders caused by germline mutations in genes that encode components acting in the RAS/MAPK pathway. Among RASopathies, NS/LAH (OMIM 607721) is an extremely rare, multiple anomaly syndrome characterized by dysmorphic facial features similar to those observed in Noonan syndrome along with some distinctive ectodermal findings including easily pluckable, sparse, thin, and slow‐growing hair. ADA2 deficiency (DADA2, OMIM 615688) is a monogenic autoinflammatory disorder caused by homozygous or compound heterozygous mutations in ADA2, with clinical features including recurrent fever, livedo racemosa, hepatosplenomegaly, and strokes as well as immune dysregulation. This is the first report of NS/LAH and ADA2 deficiency in the same individual. We report on a patient presenting with facial features, recurrent infections and ectodermal findings in whom both the clinical and molecular diagnoses of NS/LAH and ADA2 deficiency were established, respectively.     

Microduplication of 3p25.2 encompassing RAF1 associated with congenital heart disease suggestive of Noonan syndrome

Noonan syndrome (NS) is a clinically variable and genetically heterogeneous disorder with congenital heart defects (CHD), short stature, and craniofacial dysmorphisms. Gain-of-function mutations in RAF1 can cause NS and the highly related NS with multiple lentigines (previously known as LEOPARD syndrome). Here we report on a 15-year-old male with NS phenotype: short stature, heart defects, low posterior hairline, facial malformations, malformed left ear with sensorineural hearing loss, widely spaced nipples, and unilateral upper limb anomaly. Using high-resolution SNP array technology, we identified in this patient a 0.25?Mb microduplication at 3p25.2 in which RAF1 is located. Sequence analysis did not identify mutations in genes associated with Holt-Oram syndrome. These findings suggest that duplications of genomic regions encompassing RAF1 could cause NS and are consistent with the notion that rare copy number variations encompassing causative genes may underlie a small percentage of patients with syndromic CHD like NS.     

Co-occurring SHOC2 and PTPN11 mutations in a patient with severe/complex Noonan syndrome-like phenotype

Noonan syndrome (NS) is a heterogeneous disorder caused by activating mutations in the RAS-MAPK signaling pathway. It is associated with variable clinical expression including short stature, congenital heart defect, unusual pectus deformity, and typical facial features and the inheritance is autosomal dominant. Here, we present a clinical and molecular characterization of a patient with Noonan-like syndrome with loose anagen hair phenotype and additional features including mild psychomotor developmental delay, osteoporosis, gingival hyperplasia, spinal neuroblastoma, intrathoracic extramedullary hematopoiesis, and liver hemangioma. Mutation analysis of PTPN11, SOS1, RAF1, KRAS, BRAF, MEK1, MEK2, NRAS, and SHOC2 was conducted, revealing a co-occurrence of two heterozygous previously identified mutations in the index patient. The mutation SHOC2 c.4A > G; p.Ser2Gly represents a de novo mutation, whereas, PTPN11 c.1226G > C; p.Gly409Ala was inherited from the mother and also identified in the brother. The mother and the brother present with some NS manifestations, such as short stature, delayed puberty, keratosis pilaris, café-au-lait spots, refraction error (mother), and undescended testis (brother), but no NS facial features, supporting the notion that the PTPN11 p.Gly409Ala mutation leads to a relatively mild phenotype. We propose that, the atypical phenotype of the young woman with NS reported here is an additive effect, where the PTPN11 mutation acts as a modifier. Interestingly, co-occurrence of RAS-MAPK mutations has been previously identified in a few patients with variable NS or neurofibromatosis-NS phenotypes. Taken together, the results suggest that co-occurrence of mutations or modifying loci in the RAS-MAPK pathway may contribute to the clinical variability observed among NS patients.     

Homozygous microdeletion of the POU1F1, CHMP2B, and VGLL3 genes in chromosome 3--a novel syndrome

Microdeletion syndromes include numerous syndromic phenotypes associated with intellectual disability and dysmorphic features. We report on a patient with a novel microdeletion of chromosomal region 3p11.2-p12.1 containing POU1F1, chromatin-modifying protein 2B (CHMP2B), and vestigial-like 3 (VGLL3) genes. Our patient was diagnosed as having a neonatal multiple pituitary hormone [growth hormone (GH), thyroid-stimulating hormone (TSH), and prolactin] deficiency. In addition to the typical findings associated with these hormonal deficiencies, she exhibited clinical features resembling those of Laron syndrome (frontal bossing, saddle nose, small chin, blue sclera, and acromicria), with moderate intellectual disability. She also displayed an unusual growth pattern characterized by unresponsiveness to high doses of GH replacement therapy during infancy and early childhood and an accelerated growth rate beginning at the age of 4.5 years. Insulin-like growth factor (IGF)-1 levels were consistently extremely low or undetectable. Extensive medical and genetic analysis ruled out primary and secondary GH insensitivity. The distinct phenotype and the peculiar growth pattern observed in this affected patient, not reported to have been observed in other cases with POU1F1 gene inactivity, suggest that the other two deleted genes play a possible role in the development of this syndrome. This hypothesis may be supported by the fact that both the CHMP2B and VGLL3 genes are expressed in the liver and the growth plate, the two main target organs of the GH/IGF-1 axis. The homozygous deletion of the CHMP2B gene, previously associated with frontotemporal dementia, may contribute to the intellectual disability observed in this patient.     

Allelic variations of the D2 dopamine receptor gene in children with idiopathic short stature

The D2 dopamine receptor (DRD2) plays a major role in growth hormone (GH) secretion. Recent reports indicate that Taq I A DRD2 gene alleles (A1 and A2) are related to the function of DRD2. Idiopathic short stature (ISS) is defined as short stature without accompanying malnutrition, chronic disease, and endocrinological disorders. However, some reports suggest that ISS is associated with a mild disturbance of GH secretion. In this study, we examined the notion that allelic variants of the DRD2 are associated with ISS. We studied 55 children with ISS aged 8.4 (SD 2.9) years; (group I) and 104 age-matched children of normal stature (group II). Informed consent was obtained from each child's parent or guardian. Genomic DNAs were extracted from peripheral mononuclear cells and amplified by polymerase chain reaction (PCR). The PCR products were digested by Taq1 and resolved by electrophoresis. The frequency of the A1 allele was significantly higher in group I (0.42) than in group II (0.26). The insulin-like growth factor (IGF)-I ratio (the ratio of the individual level to the normal mean value according to age at our laboratory center) was significantly lower in group I than in group II. When group I was subdivided into group A (with the A1 allele) and group B (with only the A2 allele), group A had a significantly lower peak GH response to the l-dopa test, lower levels of IGF-I, and retarded bone maturation. These findings indicate that polymorphism of the DRD2 gene may be one genetic factor that affects body height in childhood, acting through the hypothalamus (GH-releasing hormone) — pituitary (GH) — IGF-I axis. Received: July 13, 1998 / Accepted: September 9, 1998     

Spectrum of mutations in PTPN11 and genotype-phenotype correlation in 96 patients with Noonan syndrome and five patients with cardio-facio-cutaneous syndrome

Noonan syndrome (NS) is a relatively common, but genetically heterogeneous autosomal dominant malformation syndrome. Characteristic features are proportionate short stature, dysmorphic face, and congenital heart defects. Only recently, a gene involved in NS could be identified. It encodes the non-receptor protein tyrosine phosphatase SHP-2, which is an important molecule in several intracellular signal transduction pathways that control diverse developmental processes, most importantly cardiac semilunar valvulogenesis. We have screened this gene for mutations in 96 familial and sporadic, well-characterised NS patients and identified 15 different missense mutations in a total of 32 patients (33%), including 23 index patients. Most changes clustered in one exon which encodes parts of the N-SH2 domain. Five of the mutations were recurrent. Interestingly, no mutations in the PTPN11 gene were detected in five additional patients with cardio-facio-cutaneous (CFC) syndrome, which shows clinical similarities to NS.     

Tall stature and duplication of the insulin-like growth factor I receptor gene

Trisomy of 15q26-qter is frequently associated with tall stature and mental retardation. Here we describe a patient with such trisomy, without a partial monosomy of another chromosome. The tall stature in this patient is most probably caused by duplication of the IGF1R gene. A duplication of the IGF1R gene is not a frequent finding in patients with tall stature. In 38 patients with features of Sotos syndrome without NSD1 alterations, a duplication was found only once. This patient was already known to have an unbalanced 2;15 translocation. Looking for a duplication of the 15qter region is still worth consideration in patients with tall stature and features of Sotos syndrome without an NSD1 alteration, especially when there is craniosynostosis or marked speech delay.     

A neuronal gene mutation that kills glia

Kalina MA, Kalina‐Faska B, Paprocka J, Jamroz E, Pyrkosz A, Marsza? E, Ma?ecka‐Tendera E. Do children with Adams‐Oliver syndrome require endocrine follow‐up? New information on the phenotype and management. Adams‐Oliver syndrome (AOS) is a rare genetic condition in which the main diagnostic criteria are terminal transverse limb defects and aplasia cutis congenita. Within the spectra of the clinical phenotype of AOS, anthropometric abnormalities have also been reported. We present growth pattern along with hormonal assays in three patients with AOS, one being treated with growth hormone (GH). In Patient 1 (a boy, age 1.9 years), with delayed psychomotor development, epilepsy, deficits of body mass and height, cryptorchidism, low insulin‐like growth factor (IGF‐1) levels were found and magnetic resonance imaging (MRI) revealed hypoplasia of midline structures of the central nervous system (CNS). In Patient 2 (a girl, age 3.6 years) no significant abnormalities in development, body mass, height or neuroimaging were found. In Patient 3 (a girl, age 8.2 years), with delayed psychomotor development and short stature, low IGF‐1 levels and partial GH deficiency were found; MRI revealed small pituitary and polymicrogyria. The girl started GH treatment, improving height velocity and gross coordination. Based on these observations, it seems that intensity of auxologic and hormonal deficits in children with AOS is associated with CNS lesions. Hence, there are indications for neuroimaging and interdisciplinary follow‐up of psychomotor development, growth and puberty in this subset of patients with AOS.     

Intragenic deletions of the IGF1 receptor gene in five individuals with psychiatric phenotypes and developmental delay

Haploinsufficiency of the gene encoding the insulin-like growth factor 1 receptor (IGF1R), either caused by telomeric 15q26 deletions, or by heterozygous point mutations in IGF1R, segregate with short stature and various other phenotypes, including microcephaly and dysmorphic facial features. Psychomotor retardation and behavioral anomalies have been seen in some cases. Here we report small, intragenic deletions of IGF1R, identified by chromosome microarray analysis in two unrelated families affected primarily with neuropsychiatric phenotypes including developmental delay, intellectual disability and aggressive/autoaggressive behaviors. The deletions are in frame, and both wild-type and mutant mRNAs are expressed as measured by quantitative real-time PCR. While short stature is considered a phenotypic hallmark of IGF1R haploinsufficiency, the present report suggests that in frame exon deletions of IGF1R present predominantly with cognitive and neuropsychiatric phenotypes.     

A New Homozygous IGF1R Variant Defines a Clinically Recognizable Incomplete Dominant form of SHORT Syndrome

Here, we describe a child, born from consanguineous parents, with clinical features of SHORT syndrome, high IGF1 levels, developmental delay, CNS defects, and marked progeroid appearance. By exome sequencing, we identified a new homozygous c.2201G>T missense mutation in the IGF1R gene. Proband's parents and other relatives, all heterozygous carriers of the mutation, presented with milder phenotype including high IGFI levels, short stature, and type 2 diabetes. Functional studies using patient's cell lines showed a lower IGF1R expression that leads to the alteration of IGF1R‐mediated PI3K/AKT/mTOR downstream pathways, including autophagy. This study defines a clinically recognizable incomplete dominant form of SHORT syndrome, and provides relevant insights into the pathophysiological and phenotypical consequences of IGF1R mutations.     

Case of 15q26-qter deletion associated with a Prader-Willi phenotype

Prader-Willi syndrome (PWS) is one of the common neurogenetic disorders associated with intellectual disability. PWS involves a complex inheritance pattern and is caused by an absence of gene expression on the paternally inherited 15q11.2-q13 region, either due to deletion, maternal uniparental disomy or imprinting defect. The syndrome is characterized principally by severe neonatal hypotonia, a weak suck in infancy that is later followed by hyperphagia and obesity, developmental delay, intellectual disability and short stature. In the case of the chromosome 15q26-qter deletion syndrome or Drayer's syndrome, very few reports have been published. Its characteristics include intrauterine growth restriction, postnatal growth failure, varying degrees of intellectual disability, developmental delay, typical facial appearance and diaphragmatic hernia. The present paper describes a female patient in whom clinical findings were suggestive of PWS and deletion in the 15q26-qter region. Both karyotyping and methylation-specific polymerase chain reaction were shown to be normal. Nevertheless, fluorescence in situ hybridization showed a 15qter deletion that was later mapped by single nucleotide polymorphism (SNP)-array. The deleted genomic region involves the insulin-like growth factor-1 receptor (IGF1R) gene, which is related to short stature, developmental delay and intellectual disability. This case had various clinical characteristics in common with the cases of 15q26-qter deletionand characteristics compatible with PWS.     

Beckwith-Wiedemann syndrome in a child with chromosome 18q deletion.

Molecular genetic investigation of a female infant with Beckwith-Wiedemann syndrome (BWS) showed loss of IGF2 imprinting but no evidence of uniparental disomy. In addition, a deletion of chromosome 18q22.1 was identified in this infant without clinical features of 18q-syndrome (microcephaly, short stature, hypotonia). The association of a chromosome 18 deletion and BWS may be coincidental or may indicate the location of a trans activating regulator element for maintenance of IGF2 imprinting.     

Clinical variability in a Noonan syndrome family with a new PTPN11 gene mutation

Noonan syndrome (NS) is an autosomal dominant disorder comprising short stature, facial dysmorphism, short and/or webbed neck, heart defects, and cryptorchidism in males. The gene responsible for the disorder (PTPN11) was recently identified, and explains 30-50% of the cases clinically diagnosed as NS. Cardiofaciocutaneous (CFC) syndrome, a similar but distinct entity, is characterized by relative macrocephaly, characteristic facial appearance, ectodermal abnormalities (sparse and friable hair, sparse eyebrows, hyperkeratotic skin), congenital heart defects, and growth and mental retardation. We describe on a young woman who presents clinical features of NS (short stature, triangular facies, with downslanting palpebral fissures and apparent hypertelorism, webbed neck, pulmonary stenosis, bleeding diathesis, prominent corneal nerves), but with a more prominent ectodermal involvement (sparse and very coarse hair, sparse eyebrows and eyelashes) and developmental delay/mental retardation, which are characteristic of CFC patients. Sequencing of the PTPN11 gene showed a T411M substitution, not previously described in patients with NS. The same mutation was found in her mother and older sister, not initially considered to be affected by NS, but with very subtle clinical findings compatible with this diagnosis. Molecular dynamic studies indicate that this new mutation, similar to other previously described mutations, favors a more active protein conformation. However, the main disruptive effect is not directly in the catalytic domain, suggesting that the location of this mutation could make the protein more susceptible to gene-gene or gene-environment interactions. Atypical cases of NS should be screened for mutations in the PTPN11 gene and in the case of a positive result, first-degree relatives should also be tested for the specific mutation.     

Germinal mosaicism in Noonan syndrome: A family with two affected siblings of normal parents

Noonan syndrome (NS; OMIM 163950) is an autosomal dominant disorder with variable clinical expression and genetic heterogeneity. Clinical manifestations include characteristic facial features, short stature, and cardiac anomalies. Mutations in protein-tyrosine phosphatase, non-receptor-type 11 (PTPN11), encoding SHP-2, account for about half of NS patients. We report on a Moroccan family with two children with NS and apparently unaffected parents. The molecular studies showed the heterozygous mutation c.922A>G of PTPN11 gene in the two affected sibs. Neither the parents, nor the oldest brother carries this mutation in hematologic cells. The mutation was also absent in buccal epithelial cells and fingernails of both parents. We believe this is the first report of germ cell mosaicism in NS and suggest an empirical risk for recurrence of that is less than 1%.     

Endocrine abnormalities in patients with Jacobsen (11q-) syndrome

Jacobsen syndrome (JS), a rare disorder with multiple dysmorphic features, is caused by the terminal deletion of chromosome 11q. Short stature has been reported in this syndrome, however very few of these patients have undergone endocrine evaluation. Serum insulin-like growth factor-1 (IGF-1) levels are an indirect indicator of growth hormone activity and are a useful initial screening tool in the assessment of an individual's growth hormone axis. We studied nine children with JS, eight of whom had short stature. Four out of eight children with short stature (50%) had low IGF-1 values, with three low for age and one low for Tanner stage. Four out of six males (67%) had cryptorchidism, a potential sign of hypogonadism. We conclude that low IGF-1 is common in patients with JS and short stature, and that growth hormone status and possibly hypothalamic-pituitary function should be evaluated in this patient population.     

Short stature and growth hormone deficiency in a subset of patients with Potocki–Lupski syndrome: Expanding the phenotype of PTLS

Potocki–Lupski Syndrome (PTLS, MIM 610883), or duplication of chromosome 17p11.2, is a clinically recognizable condition characterized by infantile hypotonia, failure to thrive, developmental delay, intellectual disability, and congenital anomalies. Short stature, classified as greater than two standard deviations below the mean, has not previously been considered a major feature of PTLS. Retrospective chart review on a cohort of 37 individuals with PTLS was performed to investigate the etiology of short stature. Relevant data included anthropometric measurements, insulin growth factor‐1 (IGF‐1), insulin‐like growth factor binding protein 3 (IGFBP‐3), growth hormone (GH) stimulation testing, blood glucose levels, brain MRI, and bone age. Approximately 25% (9/37) of individuals with PTLS had short stature. Growth hormone deficiency (GHD) was definitively identified in two individuals. These two PTLS patients with growth hormone deficiency, as well as three others with short stature and no documented GHD, received growth hormone and obtained improvement in linear growth. One individual was identified to have pituitary abnormalities on MRI and had complications of hypoglycemia due to unrecognized GHD. Individuals with PTLS can benefit from undergoing evaluation for GHD should they present with short stature or hypoglycemia. Early identification of GHD could facilitate potential therapeutic benefit for individuals with PTLS, including linear growth, musculoskeletal, and in cases of hypoglycemia, potentially cognitive development as well.     

A case report of Noonan syndrome‐like disorder with loose anagen hair 2 treated with recombinant human growth hormone

Protein phosphatase 1 catalytic subunit beta (PPP1CB) is a disease‐causing gene of Noonan‐like syndrome, which acts via the RAS/MAPK pathway. To date, only 17 patients diagnosed with PPP1CB‐related Noonan‐like syndrome have been reported around the world, with few reports in Asia. Twelve reported patients are of short stature and only one patient was treated with growth hormone (GH); however, follow‐up data is lacking. To the best of our knowledge, this is the first reported patient with complete recombinant human growth hormone (rhGH) treatment follow‐up data; the patient has a de novo c.146C>G (p.Pro49Arg) mutation in the PPP1CB gene. The hair pattern of the patient (coarse, curly, slow growing, and fragile) combined with Noonan dysmorphic features, developmental delay, and congenital heart disease, are highly consistent with the typical features observed in Noonan syndrome‐like disorder with loose anagen hair 2 (NSLH2). rhGH treatment, administered for 3 years and 8 months, promoted the patient's linear growth. Our findings expand the data regarding the treatment of short stature in patients with NSLH2 caused by PPP1CB mutation. Clinical manifestation, growth and development process, and rhGH therapy effect data will aid in future revision of the relevant diagnosis and treatment guidelines.