A comprehensive review of reported heritable noggin-associated syndromes and proposed clinical utility of one broadly inclusive diagnostic term: NOG-related-symphalangism spectrum disorder (NOG-SSD)

The NOG gene encodes noggin, a secreted polypeptide that is important for regulating multiple signaling pathways during human development, particularly in cartilage and bone. The hallmark of NOG-related syndromes is proximal symphalangism, defined by abnormal fusion of the proximal interphalangeal joints of the hands and feet. Many additional features secondary to NOG mutations are commonly but inconsistently observed, including a characteristic facies with a hemicylindrical nose, congenital conductive hearing loss due to stapes fixation, and hyperopia. The variable clinical presentations led to the designation of five different autosomal dominant syndromes, all subsequently found to have resulted from NOG mutations. These include (1) proximal symphalangism; (2) multiple synostoses syndrome 1; (3) stapes ankylosis with broad thumbs and toes; (4) tarsal-carpal coalition syndrome; and (5) brachydactyly type B2. Herein, we review the phenotypic features associated with mutations in the NOG gene, demonstrating the overlapping characteristics of these syndromes. Due to the variable phenotypic spectrum within families and among families with the same mutation, we propose a unifying term, NOG-related symphalangism spectrum disorder (NOG-SSD), to aid in the clinical recognition and evaluation of all affected individuals with these phenotypes. These NOG gene variants are available in a new locus-specific database (https://NOG.lovd.nl).     

Mutations of the NOG gene in individuals with proximal symphalangism and multiple synostosis syndrome

Proximal symphalangism is an autosomal-dominant disorder with ankylosis of the proximal interphalangeal joints, carpal and tarsal bone fusion, and conductive deafness. These symptoms are shared by another disorder of joint morphogenesis, multiple synostoses syndrome. Recently, it was reported that both disorders were caused by heterozygous mutations of the human noggin gene (NOG). To date, seven mutations of NOG have been identified from unrelated families affected with joint morphogenesis. To characterize the molecular lesions of proximal symphalangism, we performed analyses of NOG in three Japanese individuals with proximal symphalangism. We found three novel mutations: g.551G>A (C184Y) in a sporadic case of symphalangism, g.386T>A (L129X) in a familial case of symphalangism, and a g.58delC (frameshift) in a family with multiple synostosis syndrome. Characteristic genotype-phenotype correlations have not been recognized from the mutations in the NOG gene.     

Proximal symphalangism with “coarse” facial appearance,mixed hearing loss,and chronic renal failure: New malformation syndrome?

A 25‐year‐old man is described with short stature, moderate mental retardation, an abnormal facial appearance, a webbed neck, skeletal abnormalities including proximal symphalangism of bilateral second through fifth fingers, mixed hearing loss, and slowly progressive, sclerosing nephropathy. He was large at birth with generalized edema, more pronounced around the jaw, neck and the upper part of the body, but became short with increasing age, and currently measures 143 cm (−4.9 SD). He had intermittent proteinuria and slowly progressive deterioration of the renal function. A biopsy of the left kidney showed global glomerular sclerosis with interstitial fibrosis. He was placed on maintenance peritoneal dialysis at age 17 years, and now on hemodialysis. His skeletal abnormalities included, in addition to proximal symphalangism, stenosis of the cervical canal, scoliosis, brachydactyly of the hands, hypoplastic hip joints, and pes valgus. Other abnormalities noted were a communicating defects of the diaphragm (surgically corrected), bilateral inguinal hernia and cryptorchidism. These clinical manifestations indicate a hitherto undescribed combination of manifestations and nephropathy. © 2001 Wiley‐Liss, Inc.     

Skin mastocytosis with short stature, conductive hearing loss and microtia: a new syndrome

A 5 1/2-year-old Sephardic Jewish girl, born of consanguineous parents, is described. She has short stature, microcephaly, conductive hearing loss, skin mastocytosis and microtia. Since this constellation of findings has not been reported previously, we think that these findings represent a new congenital malformation, most probably of genetic etiology.     

Evolution of the phenotype of craniosynostosis with dental anomalies syndrome and report of IL11RA variant population frequencies in a Crouzon‐like autosomal recessive syndrome

In 2011, biallelic loss‐of‐function variants in the interleukin receptor 11 alpha gene IL11RA were found to be associated with a Crouzon‐like craniosynostosis syndrome with associated dental anomalies (CRSDA). Since then, a total of 41 similar patients have been reported with IL11RA variants. We report two adult brothers diagnosed with Crouzon syndrome as children, in which the clinical diagnosis of CRSDA was made on reevaluation. Laboratory testing detected biallelic IL11RA variants, c.916_924dup (p.Thr306_Ser308dup) and c.781C > T (p.Arg261Cys), both of which have now been reported in other families. Protein modeling and conservation analysis show that these two mutation sites cluster together near a WSXWS motif that likely plays a significant role in regulating IL11RA protein function. Population analysis from gnomAD shows that Non‐Finnish Europeans (similar to ethnicity of this family), have an allele frequency for p.Thr306_Ser308dup of 0.014% and p.Arg261Cys of 0.008%. We found other ethnicities have functional IL11RA missense variants at higher frequencies. With this report, we provide a summary of the clinical findings including details of middle ear anomalies associated with conductive hearing loss. We also provide data supporting the populations at risk for this condition to increase recognition and diagnosis of this rare autosomal recessive craniosynostosis syndrome.     

De novo complete trisomy 5p: Clinical and neuroradiological findings

A Thai mother and son with distal symphalangism and other associated abnormalities are reported. Distal and middle phalanges of fingers and toes 2–5 were either aplastic/hypoplastic or fused between the corresponding digits. The second fingers and fourth fingernails were most severely affected in both patients. The mother's hands were less severely affected; the middle and distal phalanges of her hands were malformed and fused. Besides the absence of fusion lines, the shape of the fused middle and distal phalanges was quite different from that of other types of fusion, i.e., fused bones in both patients did not maintain the normal configuration of bone, referring to as “middle‐distal phalangeal complex”. Distal symphalangism was observed in toes 2–5 of the mother and in toe 3 of the son. Both patients had additional clinical manifestations such as narrowing of the zygomatic arch, dental pulp stone, microdontia of a mandibular permanent central incisor, cone‐shaped epiphyses of middle phalanges of fingers, and absence of scaphoid, trapezium, trapezoid, and pisiform bones. Mutation analysis of NOG and ROR2, the genes responsible for proximal symphalangism and brachydactyly type B, respectively, was negative. © 2002 Wiley‐Liss, Inc.     

Multiple and bilateral kidney tumors with clear cells of three different histotypes: A case report with clinicopathologic and molecular study

We describe a rare multicentric neoplastic disease arising bilteraly in the kidney. The patient was a 70‐year‐old man, who, during a period of 3 years, was treated for five independent tumors of three histotypes (three multilocular cystic clear cell renal cell neoplasms of low malignant potential, one clear cell renal cell carcinoma, and one clear cell papillary renal cell carcinoma, respectively). Pathologic diagnosis of the reported tumors was confirmed by immunohistochemical analyses, including CD10, CA IX, CK7, AMACR/RACEMASE, and 34 beta E12. Molecular detection of KRAS, BRAF, NRAS, PIK3CA, ALK, ERBB2, DDR2, MAP2K1, RET, and EGFR gene mutational analysis was also performed in all tumors.     

Waardenburg syndrome type II: Phenotypic findings and diagnostic criteria

The Waardenburg syndrome (WS) consists of at least two distinct autosomal dominant hereditary disorders. WS Type I has been mapped to the distal part of chromosome 2q and the gene identified as PAX3. Other gene(s) are responsible for WS Type II. Mapping WS Type II requires accurate diagnosis within affected families. To establish diagnostic criteria for WS Type II, 81 individuals from 21 families with Type II WS were personally studied, and compared with 60 personally studied patients from 8 families with Type I and 253 cases of WS (Type I or II) from the literature. Sensorineural hearing loss (77%) and heterochromia iridum (47%) were the two most important diagnostic indicators for WS Type II. Both were more common in Type II than in Type I. Other clinical manifestations, such as white forelock and skin patches, were more frequent in Type I. We estimate the frequency of phenotypic traits and propose diagnostic criteria for WS Type II. In practice, a diagnosis of WS Type II can be made with confidence given a family history of congenital hearing loss and pigmentary disorders, where individuals have been accurately measured for ocular distances to exclude dystopia canthorum. © 1995 Wiley-Liss, Inc.     

Three new cases of spondylocarpotarsal synostosis syndrome: Clinical and radiographic studies

Spondylocarpotarsal synostosis syndrome (SSS) or congenital synspondylism is a recently delineated clinical entity. At least 15 patients have been reported. We present 3 new patients, 2 of whom were sibs born to first-cousin parents. All of our patients had multiple synostoses involving cervical, thoracic and/or lumbar vertebral bodies and carpal/tarsal bones, scoliosis/lordosis, and short stature. Sensorineural deafness was found in 2 of the 3 patients. Analysis of clinical manifestations suggests clinical variability and genetic heterogeneity in SSS. Of a total of 18 SSS patients, 10 were five pairs of sibs from five families, with first-cousin consanguinity of parents in 3, indicating that at least one type of SS is an autosomal-recessive disorder. Am. J. Med. Genet. 77:12–15, 1998. © 1998 Wiley-Liss, Inc.     

Multiple organ dysfunction syndrome,an unusual complication of heroin intoxication: a case report and review of literature

Multiple organ dysfunction syndrome (MODS) has rarely been described in patients with heroin intoxication. Here, we report a rare case of MODS involving six organs, due to heroin intoxication. The patient was a 32-year-old Chinese man with severe heroin intoxication complicated by acute pulmonary edema and respiratory insufficiency, shock, myocardial damage and cardiac insufficiency, rhabdomyolysis and acute renal insufficiency, acute liver injury and hepatic insufficiency, toxic leukoencephalopathy, and hypoglycemia. He managed to survive and was discharged after 10 weeks of intensive care. The possible pathogenesis and therapeutic measures of MODS induced by heroin intoxication and some suggestions for preventing and treating severe complications of heroin intoxication, based on clinical evidence and the pertinent literature, are discussed in this report.     

Clinical,molecular, and pathological findings in a Neu–Laxova syndrome stillborn: A Brazilian case report

Neu–Laxova syndrome (NLS) is a lethal genetic multiple congenital anomaly syndrome of unknown prevalence representing the severe spectrum of serine biosynthesis defects associated with PHGDH, PSAT1, or PSP gene mutations. The purpose of this study was to describe clinical/molecular and pathologic features of a NLS case caused by novel heterozygous missense variant in PHGDH gene identified in his consanguineous parents.     

一例新生儿甲状旁腺功能减低-感音神经性耳聋-肾发育不良综合征患儿的临床及遗传学分析CSCD

目的分析甲状旁腺功能减低-感音神经性耳聋-肾发育不良(hypoparathyroidism-sensorineural deafness-renal dysplasia, HDR)综合征的临床表型与基因变异特点。方法对1例HDR综合征新生儿进行全基因组拷贝数变异(copy number variation, CNVs)以及外显子组检测, 并分析其临床资料和相关文献。结果患儿为男性, 新生儿期起病, 表现为特殊面容、通贯掌、骶尾部赘生物。血清学检查提示低钙血症、低甲状旁腺激素。听力检测提示双侧感音神经性耳聋。超声检查提示右肾缺如, CNVs检测提示染色体10p15.3-p13(chr10: 105 001_12 815 001)区存在12.71 Mb的缺失, 全外显子测序提示GATA3基因缺失。患儿经补充钙剂及维生素D治疗, 病情有所好转。结论患儿的10p15.3-p13缺失与甲状旁腺功能减退、感音神经性耳聋和右肾缺如等临床表型相关。HDR综合征是罕见的遗传性疾病, 应提高对其的认识, 减少漏诊。     

Multiple giant cell lesions in patients with Noonan syndrome and cardio-facio-cutaneous syndrome

Noonan syndrome (NS) and cardio-facio-cutaneous syndrome (CFCS) are related developmental disorders caused by mutations in genes encoding various components of the RAS-MAPK signaling cascade. NS is associated with mutations in the genes PTPN11, SOS1, RAF1, or KRAS, whereas CFCS can be caused by mutations in BRAF, MEK1, MEK2, or KRAS. The NS phenotype is rarely accompanied by multiple giant cell lesions (MGCL) of the jaw (Noonan-like/MGCL syndrome (NL/MGCLS)). PTPN11 mutations are the only genetic abnormalities reported so far in some patients with NL/MGCLS and in one individual with LEOPARD syndrome and MGCL. In a cohort of 75 NS patients previously tested negative for mutations in PTPN11 and KRAS, we detected SOS1 mutations in 11 individuals, four of whom had MGCL. To explore further the relevance of aberrant RAS-MAPK signaling in syndromic MGCL, we analyzed the established genes causing CFCS in three subjects with MGCL associated with a phenotype fitting CFCS. Mutations in BRAF or MEK1 were identified in these patients. All mutations detected in these seven patients with syndromic MGCL had previously been described in NS or CFCS without apparent MGCL. This study demonstrates that MGCL may occur in NS and CFCS with various underlying genetic alterations and no obvious genotype-phenotype correlation. This suggests that dysregulation of the RAS-MAPK pathway represents the common and basic molecular event predisposing to giant cell lesion formation in patients with NS and CFCS rather than specific mutation effects.     

Clinical and genetic studies in Spanish patients with Usher syndrome type II: description of new mutations and evidence for a lack of genotype--phenotype correlation

Patients with Usher syndrome type II (USH2) show moderate-to-severe hearing loss (HL), retinitis pigmentosa and normal vestibular function. The progression of HL remains controversial. To evaluate whether a phenotype-genotype correlation exists regarding the issue of progression of HL, only USH2 patients with a defined genotype were selected. Ophthalmologic, vestibular and audiometric examination along with a mutation analysis of the USH2A gene (exons 1--21) was performed in twenty-eight Spanish USH2 patients. Ten different pathogenic mutations and 17 sequence variants not associated with the disease were found. Six of the 10 mutations are novel. Disease alleles were identified in 13 of the 28 families tested. Eight of these 13 families had a mutation found in both alleles. In the other five families, only one mutation was identified. The phenotypic data provide evidence for the existence of phenotypic differences between patients with the same genotype. These differences were observed at both the interfamilial and intrafamilial levels.     

Multiple pterygium syndrome: a case complicated by malignant hyperthermia

The autosomal recessive multiple pterygium syndromes are a heterogeneous group of disorders in which multiple joint contractures are associated with cutaneous webbing. Recently, we evaluated a 33 week gestation male in whom multiple pterygia were one feature of a broader pattern of malformation. Clinical management was adversely affected by malignant hyperthermia. In this report we present the clinical, radiographic and pathologic data of this patient and those of an affected stillborn female sibling. We believe that these represent the features of a newly recognized disorder.     

CHRNG‐related nonlethal multiple pterygium syndrome: Muscle imaging pattern and clinical,histopathological, and molecular genetic findings

Mutations in the CHRNG gene cause autosomal recessive multiple pterygium syndrome (MPS). Herein we present a long‐term follow‐up of seven patients with CHRNG‐related nonlethal MPS and we compare them with the 57 previously published patients. The objective is defining not only the clinical, histopathological, and molecular genetic characteristics, but also the type and degree of muscle involvement on whole‐body magnetic resonance imaging (WBMRI). CHRNG mutations lead to a distinctive phenotype characterized by multiple congenital contractures, pterygium, and facial dysmorphism, with a stable clinical course over the years. Postnatal abnormalities at the neuromuscular junction were observed in the muscle biopsy of these patients. WBMRI showed distinctive features different from other arthrogryposis multiple congenita. A marked muscle bulk reduction is the predominant finding, mostly affecting the spinal erector muscles and gluteus maximus. Fatty infiltration was only observed in deep paravertebral muscles and distal lower limbs. Mutations in CHRNG are mainly located at the extracellular domain of the protein. Our study contributes to further define the phenotypic spectrum of CHRNG‐related nonlethal MPS, including muscle imaging features, which may be useful in distinguishing it from other diffuse arthrogryposis entities.