Adult Chinese twins with Kenny-Caffey syndrome type 2: A potential age-dependent phenotype and review of literature.

Kenny-Caffey syndrome (KCS) type 2 (OMIM 127000) is a rare syndromic cause of hypoparathyroidism which is characterized by proportionate short stature, long bone abnormalities, delayed closure of anterior fontanelle, eye abnormalities, and normal intelligence. It is caused by variants in FAM111A (NM_001942519.1). In this review, we reported the first Chinese patients, a pair of monozygotic twins, with genetically confirmed KCS type 2 with over 20 years follow-up. We summarized the clinical features of 14 previously reported and genetically confirmed KCS type 2 patients; our twin patients exhibited a unique spinal manifestation which could be an important age-dependent feature of KCS type 2. In this review, over 60% KCS type 2 patients had dental problem and over 80% suffered from refractive errors or structural eye abnormalities. Therefore, early dental, ophthalmological, and orthopedic assessments are warranted for KCS type 2 patients. Micro-orchidism, previously reported in KCS type 2 patients, was also detected in our patients. The possibility of subfertility should be considered in male KCS type 2 patients. A multidisciplinary management approach for this rare syndrome is recommended.

PITX2 deficiency and associated human disease: insights from the zebrafish model.

The PITX2 (paired-like homeodomain 2) gene encodes a bicoid-like homeodomain transcription factor linked with several human disorders. The main associated congenital phenotype is Axenfeld-Rieger syndrome, type 1, an autosomal dominant condition characterized by variable defects in the anterior segment of the eye, an increased risk of glaucoma, craniofacial dysmorphism and dental and umbilical anomalies; in addition to this, one report implicated PITX2 in ring dermoid of the cornea and a few others described cardiac phenotypes. We report three novel PITX2 mutations-c.271C > T, p.(Arg91Trp); c.259T > C, p.(Phe87Leu); and c.356delA, p.(Gln119Argfs*36)-identified in independent families with typical Axenfeld-Rieger syndrome characteristics and some unusual features such as corneal guttata, Wolf-Parkinson-White syndrome, and hyperextensibility. To gain further insight into the diverse roles of PITX2/pitx2 in vertebrate development, we generated various genetic lesions in the pitx2 gene via TALEN-mediated genome editing. Affected homozygous zebrafish demonstrated congenital defects consistent with the range of PITX2-associated human phenotypes: abnormal development of the cornea, iris and iridocorneal angle; corneal dermoids; and craniofacial dysmorphism. In addition, via comparison of pitx2M64* and wild-type embryonic ocular transcriptomes we defined molecular changes associated with pitx2 deficiency, thereby implicating processes potentially underlying disease pathology. This analysis identified numerous affected factors including several members of the Wnt pathway and collagen types I and V gene families. These data further support the link between PITX2 and the WNT pathway and suggest a new role in regulation of collagen gene expression during development.

Defective mitochondrial protease LonP1 can cause classical mitochondrial disease.

LonP1 is a mitochondrial matrix protease whose selective substrate specificity is essential for maintaining mitochondrial homeostasis. Recessively inherited, pathogenic defects in LonP1 have been previously reported to underlie cerebral, ocular, dental, auricular and skeletal anomalies (CODAS) syndrome, a complex multisystemic and developmental disorder. Intriguingly, although classical mitochondrial disease presentations are well-known to exhibit marked clinical heterogeneity, the skeletal and dental features associated with CODAS syndrome are pathognomonic. We have applied whole exome sequencing to a patient with congenital lactic acidosis, muscle weakness, profound deficiencies in mitochondrial oxidative phosphorylation associated with loss of mtDNA copy number and MRI abnormalities consistent with Leigh syndrome, identifying biallelic variants in the LONP1 (NM_004793.3) gene; c.1693T > C predicting p.(Tyr565His) and c.2197G > A predicting p.(Glu733Lys); no evidence of the classical skeletal or dental defects observed in CODAS syndrome patients were noted in our patient. In vitro experiments confirmed the p.(Tyr565His) LonP1 mutant alone could not bind or degrade a substrate, consistent with the predicted function of Tyr565, whilst a second missense [p.(Glu733Lys)] variant had minimal effect. Mixtures of p.(Tyr565His) mutant and wild-type LonP1 retained partial protease activity but this was severely depleted when the p.(Tyr565His) mutant was mixed with the p.(Glu733Lys) mutant, data consistent with the compound heterozygosity detected in our patient. In summary, we conclude that pathogenic LONP1 variants can lead to a classical mitochondrial disease presentations associated with severe biochemical defects in oxidative phosphorylation in clinically relevant tissues.

Novel compound heterozygous TMEM67 variants in a Vietnamese family with Joubert syndrome: a case report.

BACKGROUND: Joubert syndrome is a genetically heterogeneous autosomal recessive ciliopathy characterized by the combination of hypoplasia/aplasia of the cerebellar vermis, thickened and elongated superior cerebellar peduncles and a deep interpeduncular fossa, known as "molar tooth sign" associated with hypotonia, respiratory control disturbances and abnormal eye movements. To date, pathogenic variants in over 35 genes are known to cause autosomal recessive Joubert Syndrome, while one gene is associated with X-linked recessive inheritance. CASE PRESENTATION: We describe here a non-consanguineous Vietnamese family with Joubert syndrome, a fetus and 10-year-old developmentally delayed boy. Ultrasonography showed ventriculomegaly at 26 + 6 weeks of gestation in the fetus. The 10-year-old-boy was diagnosed with cerebral palsy of unknown origin. Clinical physical examination at the age of 10, he showed clinical features of Joubert syndrome including typical facial dysmorphism, ataxia, severe psychomotor delay, oculomotor apraxia and molar tooth sign on brain MRI. Whole exome sequencing analysis identified a novel compound heterozygous c.725A > G p.Asn242Ser and c.313-3 T > G p.Lys105Valfs*16 TMEM67 variant in the proband and the affected fetus. These two variants were inherited from each parent and confirmed by Sanger sequencing. The variant c.725A > G p.Asn242Ser was previously documented in patients with JS, the novel splice-site c.313-3 T > G p.Lys105Valfs*16 TMEM67 variant produced an aberrant transcript with the loss of four nucleotides of exon 03. CONCLUSION: This study confirms the diagnosis of Joubert syndrome in a Vietnamese family and expands the mutational spectrum of TMEM67 sequence variations. We also highlight the importance of molecular approaches to unravel underlying mechanisms of human genetic disorders. Early precise diagnosis could help provide further accurate genetic counseling for recurrence-risk assessment, future diagnostic option, management as well as treatment guidance for rare disorders.

A large deletion spanning PITX2 and PANCR in a Chinese family with Axenfeld-Rieger syndrome.

Purpose: To identify the genetic cause in a four-generation Chinese family with Axenfeld-Rieger syndrome (ARS). Methods: The family members received clinical examinations of the eye, tooth, periumbilical skin, and heart. Sanger sequencing and whole-exome sequencing (WES) were performed to screen potential mutations. The genomic deletion region around the PITX2 gene was estimated from single nucleotide polymorphism (SNP) data from WES and then confirmed with "quantitative PCR (qPCR) using a set of primers. The DNA breakpoint was further identified with long-range PCR and Sanger sequencing. Results: Symptoms including anterior segment dysplasia of the eye (iris dysplasia, multiple pupils, and posterior embryotoxon), dental dysplasia, and periumbilical skin redundancy were present in all of the affected individuals. Three of them had glaucoma. Corneal abnormalities (inferior sclerocornea, corneal endothelial dystrophy, and central corneal scar) were seen in most of the affected individuals. Cataract, limited eye movement, electrocardiographic abnormalities, intellectual disability, and recurrent miscarriages were observed in some of the affected individuals. No mutations in the coding and exon-intron adjacent regions of the PITX2 and FOXC1 genes were identified with Sanger sequencing. According to the SNP data from WES, we suspected that there might be a deletion region (at most 1.6 Mb) around the PITX2 gene. With the use of qPCR and long-range PCR, we identified a 53,840 bp deletion (chr4: 111,535,454-111,588,933) spanning PITX2 and PANCR. The genomic deletion cosegregated with the major ARS symptoms observed in the family members. Conclusions: With the help of WES, qPCR, and long-range PCR, we identified a genomic deletion encompassing PITX2 and the adjacent noncoding gene PANCR in a Chinese family with ARS. The clinical features of the affected individuals are reported. This work may broaden understanding of the phenotypic and mutational spectrums related to ARS.

Cole-Carpenter syndrome in a patient from Thailand.

Cole-Carpenter syndrome (CCS), commonly classified as a rare type of osteogenesis imperfecta, is a disorder with severe bone fragility, craniosynostosis, and distinct facial features. Recently, the heterozygous missense mutation, c.1178A>G, p.Tyr393Cys, in exon 9 of P4HB which encodes protein disulfide isomerase, has been found in three Caucasian patients with CCS. Ethnic background is known to affect clinical manifestations, especially facial features of dysmorphic syndromes. Here, we describe the first Asian CCS patient possessing the recurrent mutation in P4HB. Although she had several common features of CCS including bulging forehead, ocular proptosis, midface hypoplasia, long bone deformity, popcorn epiphyses, vertebral fractures, and scoliosis, she did not have hydrocephalus, wormian bones, and dentinogenesis imperfecta, commonly seen in Caucasian patients. Interestingly, she is the only one without macrocephaly. Radiologically, metadiaphyseal fractures of the long bones with metaphyseal sclerosis were found, substantiating that they provide a definitive radiological feature of CCS. In addition, we showed for the first time a three-dimensional facial scan of a patient with CCS. She had been given intravenous bisphosphonate since the age of 9 months and had responded well. Our study presents the clinical features of the first Asian patient, supports metaphyseal scleroses and fractures as radiological clues, strengthens early bisphosphonate administration, and confirms the etiologic role of the c.1178A>G variant in P4HB across populations.

Molecular genetic findings and clinical correlations in 100 patients with Joubert syndrome and related disorders prospectively evaluated at a single center.

PURPOSE: Joubert syndrome (JS) is a genetically and clinically heterogeneous ciliopathy characterized by distinct cerebellar and brainstem malformations resulting in the diagnostic "molar tooth sign" on brain imaging. To date, more than 30 JS genes have been identified, but these do not account for all patients. METHODS: In our cohort of 100 patients with JS from 86 families, we prospectively performed extensive clinical evaluation and provided molecular diagnosis using a targeted 27-gene Molecular Inversion Probes panel followed by whole-exome sequencing (WES). RESULTS: We identified the causative gene in 94% of the families; 126 (27 novel) unique potentially pathogenic variants were found in 20 genes, including KIAA0753 and CELSR2, which had not previously been associated with JS. Genotype-phenotype correlation revealed the absence of retinal degeneration in patients with TMEM67, C5orf52, or KIAA0586 variants. Chorioretinal coloboma was associated with a decreased risk for retinal degeneration and increased risk for liver disease. TMEM67 was frequently associated with kidney disease. CONCLUSION: In JS, WES significantly increases the yield for molecular diagnosis, which is essential for reproductive counseling and the option of preimplantation and prenatal diagnosis as well as medical management and prognostic counseling for the age-dependent and progressive organ-specific manifestations, including retinal, liver, and kidney disease.Genet Med advance online publication 26 January 2017.

A novel mutation in the proteolytic domain of LONP1 causes atypical CODAS syndrome.

Cerebral, ocular, dental, auricular, skeletal (CODAS) syndrome is a rare autosomal recessive multisystem disorder caused by mutations in LONP1. It is characterized by intellectual disability, cataracts, delayed tooth eruption, malformed auricles and skeletal abnormalities. We performed whole-exome sequencing on a 12-year-old Japanese male with severe intellectual disability, congenital bilateral cataracts, spasticity, hypotonia with motor regression and progressive cerebellar atrophy with hyperintensity of the cerebellar cortex on T2-weighted images. We detected compound heterozygous mutation in LONP1. One allele contained a paternally inherited frameshift mutation (p.Ser100Glnfs*46). The other allele contained a maternally inherited missense mutation (p.Arg786Trp), which was predicted to be pathogenic by web-based prediction tools. The two mutations were not found in Exome Variant Server or our 575 in-house control exomes. Some features were not consistent with CODAS syndrome but overlapped with Marinesco-Sjögren syndrome, a multisystem disorder caused by a mutation in SIL1. An atypical mutation site may result in atypical presentation of the LONP1 mutation.

Molecular genetic analysis of 30 families with Joubert syndrome.

Joubert syndrome (JS) is rare recessive disorders characterized by the combination of hypoplasia/aplasia of the cerebellar vermis, thickened and elongated superior cerebellar peduncles, and a deep interpeduncular fossa which is defined by neuroimaging and is termed the 'molar tooth sign'. JS is genetically highly heterogeneous, with at least 29 disease genes being involved. To further understand the genetic causes of JS, we performed whole-exome sequencing in 24 newly recruited JS families. Together with six previously reported families, we identified causative mutations in 25 out of 30 (24 + 6) families (83.3%). We identified eight mutated genes in 27 (21 + 6) Japanese families, TMEM67 (7/27, 25.9%) and CEP290 (6/27, 22.2%) were the most commonly mutated. Interestingly, 9 of 12 CEP290 disease alleles were c.6012-12T>A (75.0%), an allele that has not been reported in non-Japanese populations. Therefore c.6012-12T>A is a common allele in the Japanese population. Importantly, one Japanese and one Omani families carried compound biallelic mutations in two distinct genes (TMEM67/RPGRIP1L and TMEM138/BBS1, respectively). BBS1 is the causative gene in Bardet-Biedl syndrome. These concomitant mutations led to severe and/or complex clinical features in the patients, suggesting combined effects of different mutant genes.

Cognitive, adaptive, and behavioral features in Joubert syndrome.

Joubert syndrome (JS) is a recessive neurodevelopmental disorder characterized by a distinctive cerebellar and brainstem malformation recognizable on brain imaging, the so-called molar tooth sign. The full spectrum of cognitive and behavioral phenotypes typical of JS is still far from being elucidated. The aim of this multicentric study was to define the clinical phenotype and neurobehavioral features of a large cohort of subjects with a neuroradiologically confirmed diagnosis of JS. Fifty-four patients aged 10 months to 29 years were enrolled. Each patient underwent a neurological evaluation as well as psychiatric and neuropsychological assessments. Global cognitive functioning was remarkably variable with Full IQ/General Quotient ranging from 32 to 129. Communication skills appeared relatively preserved with respect to both Daily Living and Socialization abilities. The motor domain was the area of greatest vulnerability, with a negative impact on personal care, social, and academic skills. Most children did not show maladaptive behaviors consistent with a psychiatric diagnosis but approximately 40% of them presented emotional and behavioral problems. We conclude that intellectual disability remains a hallmark but cannot be considered a mandatory diagnostic criterion of JS. Despite the high variability in the phenotypic spectrum and the extent of multiorgan involvement, nearly one quarter of JS patients had a favorable long-term outcome with borderline cognitive deficit or even normal cognition. Most of JS population also showed relatively preserved communication skills and overall discrete behavioral functioning in everyday life, independently from the presence and/or level of intellectual disability. © 2016 Wiley Periodicals, Inc.

Myogenic bladder defects in mouse models of human oculodentodigital dysplasia.

To date, over 65 mutations in the gene encoding Cx43 (connexin43) have been linked to the autosomal-dominant disease ODDD (oculodentodigital dysplasia). A subset of these patients experience bladder incontinence which could be due to underlying neurogenic deterioration or aberrant myogenic regulation. BSMCs (bladder smooth muscle cells) from wild-type and two Cx43 mutant lines (Cx43(G60S) and Cx43(I130T)) that mimic ODDD exhibit a significant reduction in total Cx43. Dye transfer studies revealed that the G60S mutant was a potent dominant-negative inhibitor of co-expressed Cx43, a property not equally shared by the I130T mutant. BSMCs from both mutant mouse strains were defective in their ability to contract, which is indicative of phenotype changes due to harbouring the Cx43 mutants. Upon stretching, Cx43 levels were significantly elevated in controls and mutants containing BSMCs, but the non-muscle myosin heavy chain A levels were only reduced in cells from control mice. Although the Cx43(G60S) mutant mice showed no difference in voided urine volume or frequency, the Cx43(I130T) mice voided less frequently. Thus, similar to the diversity of morbidities seen in ODDD patients, genetically modified mice also display mutation-specific changes in bladder function. Furthermore, although mutant mice have compromised smooth muscle contraction and response to stretch, overriding bladder defects in Cx43(I130T) mice are likely to be complemented by neurogenic changes.

Developmental disorders of the dentition: an update.

Dental anomalies are common congenital malformations that can occur either as isolated findings or as part of a syndrome. This review focuses on genetic causes of abnormal tooth development and the implications of these abnormalities for clinical care. As an introduction, we describe general insights into the genetics of tooth development obtained from mouse and zebrafish models. This is followed by a discussion of isolated as well as syndromic tooth agenesis, including Van der Woude syndrome (VWS), ectodermal dysplasias (EDs), oral-facial-digital (OFD) syndrome type I, Rieger syndrome, holoprosencephaly, and tooth anomalies associated with cleft lip and palate. Next, we review delayed formation and eruption of teeth, as well as abnormalities in tooth size, shape, and form. Finally, isolated and syndromic causes of supernumerary teeth are considered, including cleidocranial dysplasia and Gardner syndrome.

Congenital heart defects in oculodentodigital dysplasia: Report of two cases.

Oculodentodigital dysplasia is caused by mutations in the GJA1 gene. Oculodentodigital dysplasia presents with a spectrum of clinical features including craniofacial, ocular, dental, and limb anomalies. Although recent findings implicate the major role of GJA1 during cardiac organogenesis, congenital heart defects are infrequently reported in oculodentodigital dysplasia. Here we report on two patients with GJA1 mutations presenting with cardiac malformations and type III syndactyly. Patient 1 presented with pulmonary atresia, an intact septum, right ventricular hypoplasia and tricuspid stenosis. The infant had a small nose, thin columella and bilateral 4-5 syndactyly of the fingers. A de novo c.226C>T (p.Arg76Cys) mutation was identified. Patient 2 presented at 6 months with a ventricular septal defect. The child had hypoplastic alae nasi with a thin columella and bilateral 4-5 syndactyly of the digits. A de novo missense mutation, c.145C>G (p.Gln49Glu) was found. Our two patients underscore the importance of cardiac evaluations as part of the initial workup for patients with findings of oculodentodigital dysplasia. Conversely, those patients with type III syndactyly and congenital heart defect should be screened for GJA1 mutations.

Humphrey visual fields and optical coherence tomography findings in patients with the Axenfeld-Rieger syndrome: a case series.

INTRODUCTION: Axenfeld-Rieger syndrome is characterized by clinical characteristics including: ocular, craniofacial, dental, umbilical, and other systemic abnormalities. Previous studies have reported that the Axenfeld-Rieger syndrome (ARS) occurs in one out of 200,000 patients. PURPOSE: To study patients with the ARS in a sub-urban community in Puerto Rico. PATIENTS AND METHODS: We conducted a non-concurrent study of 17,800 patients. Of these, 57 patients had the syndrome. Every patient had a comprehensive ophthalmology evaluation. RESULTS: A frequency of 320 per 100,000 was found in the studied population. Using Humphrey's visual field analyzer, we found a mean deviation of less than -2.00 dB in 56.4 and 60.5 percent of the right and left eye respectively. OCT evaluation of the optic nerve rim showed glaucomatous changes in 29.2 and 41.7 percent of the right and left eyes respectively. OCT evaluation of the retinal nerve fiber layer showed glaucomatous changes in 20.8 and 16.7 percent of the right and left eyes respectively. CONCLUSION: The frequency of patients with the syndrome in Puerto Rico is higher than in other populations reported in the literature. Also, the percent of patients with glaucoma is higher than previously reported. A relationship between hemochromatosis and ARS has not been previously described. Further studies will elucidate the genetics of Axenfeld-Rieger syndrome in Puerto Rico.

Oculodentodigital dysplasia: disease spectrum in an eight-year-old boy, his parents and a sibling.

Oculodentodigital dysplasia is an extremely rare autosomal dominant pleiotropic disorder caused by mutations in the Connexin 43 gene (GJA1). Described here is a previously undiagnosed case of an 8-year-old boy with enamel and dentin hypoplasia and typical faces. In this presentation, many typical clinical and radiographical features of this condition are present. The characteristic features include a typical face, premature loss of primary teeth and odontodysplasia of permanent teeth, clinodactyly, ocular signs, and CNS involvement. To our knowledge, the case that we report here is the first case with mamelon-shaped tip of the tongue and enlarged midpalatal raphe.

A novel PDE6D mutation in a patient with Joubert syndrome type 22 (JBTS22).

Joubert syndrome (JS) is an autosomal or X-linked recessive syndrome principally characterized by hypotonia, ataxia, cognitive impairment, and a specific finding on brain imaging called a "molar tooth sign" (MTS), which can be isolated or in conjunction with variable organ involvement. The genetic basis of JS is heterogeneous, with over 35 ciliary genes being implicated in its pathogenesis. However, some of these genes (such as PDE6D) have been associated to JS only in single families, seeking confirmation. Here we report a boy, born to first cousin parents, presenting with developmental delay, hypotonia, microcephaly, post axial polydactyly, oculomotor apraxia, and MTS. Whole exome sequencing revealed the presence of a novel homozygous truncating variant in the PDE6D gene: NM_002601.3:c.367_368insG [p.(Leu123Cysfs*13)]. The variant was confirmed by Sanger sequencing and found at the heterozygous state in both parents. A review of the literature pertaining to the role of PDE6D in JS is discussed.

The rare Axenfeld-Rieger syndrome with systemic anomalies: A case report and brief review of literature.

RATIONALE: Axenfeld-Rieger syndrome (ARS) is a rare autosomal dominant disorder with ocular anterior segment dysgenesis and systemic anomalies. PATIENT CONCERNS: A 28-year-old Chinese Han female was referred to Beijing Tongren Eye Center for progressive decrease of the visual acuity on her right eye in the past month. DIAGNOSES: The patient was diagnosed as ARS with retinal detachment based on series of ophthalmic examinations performed. INTERVENTIONS: A pars plana vitrectomy was performed to manage the retinal detachment. OUTCOMES: Her best-corrected visual acuity was slightly improved after surgery. LESSONS: ARS is a developmental defect of ocular anterior segment with various clinical manifestations which might cause misdiagnosis.

Cognitive rehabilitation in a child with Joubert Syndrome: Developmental trends and adaptive changes in a single case report.

We report the clinical and rehabilitative follow up of M, a female child carrying a compound heterozygous pathogenic mutations in the TCTN1 gene and affected by Joubert Syndrome (JS). JS is a congenital cerebellar ataxia characterized by "the molar tooth sign" on axial MRI, a pathognomonic neuroradiological malformation involving the cerebellum and brainstem. JS presents with high phenotypic/cognitive variability, and little is known about cognitive rehabilitation programs. We describe the therapeutic settings, intensive rehabilitation targets and outcome indexes in M's cognitive development. Using a single case evidence-based approach, we attempt to distinguish the effectiveness of the intervention from the overall developmental trend. We assume that an adequate amount of focused, goal directed treatment in a relative short period of time can be at least as effective as one provided in longer time, and much less interfering with the child's everyday life. We conclude by discussing specific issues in cognitive development and rehabilitation in JS and, more broadly, in cerebellar malformations.

Uncrossed epileptic seizures in Joubert syndrome.

Joubert syndrome and related disorders comprise a subgroup of ciliopathies defined by the presence of the 'molar tooth sign', a midbrain-hindbrain malformation identifiable by neuroimaging. Characteristically, the corticospinal tract and superior cerebellar peduncles do not decussate. Epileptic seizures are uncommon. We present a case of a 28-year-old man with a background of Leber's congenital amaurosis with nephronophthisis, requiring kidney transplantation, and mental retardation, who developed epileptic seizures consisting of a short muffled cry and involuntary shaking movements of the extremities beginning in the left upper limb; these episodes lasted several seconds and occurred in clusters. Simultaneous video-EEG recording showed an ictal pattern in the left frontal lobe. Brain MRI revealed the pathognomonic 'molar tooth sign'; diffusion tensor imaging (DTI)-tractography showed a lack of decussation of both corticospinal tracts. To the best of our knowledge, this is the first time that DTI-tractography has been used to uncover the anatomical substrate underlying the semiology of epileptic seizures.