Homozygous novel truncating variant of CLPP associated with severe Perrault syndrome.

A female proband and her affected niece are homozygous for a novel frameshift variant of CLPP. The proband was diagnosed with severe Perrault syndrome encompassing hearing loss, primary ovarian insufficiency, abnormal brain white matter and developmental delay.

Disgenesia gonadal pura 46 XX, una causa infrecuente de hipogonadismo: presentación de un caso / Pure gonadal dysgenesis 46 XX, an ucommon cause of hypogonadism: case presentation

El término disgenesia gonadal pura hace referencia a mujeres fenotípicas con infantilismo sexual, amenorrea primaria, hábito eunucoide y un cariotipo 46, XX o 46, XY sin anomalías cromosómicas. Puede asociarse a complicaciones como osteoporosis y síndrome metabólico, elevando el riesgo cardiovascular. Se presenta una paciente femenina de 16 años y 8 meses de edad que acude a consulta de endocrinología por presentar amenorrea primaria.

The term pure gonadal dysgenesis refers to phenotypic women with sexual infantilism, primary amenorrhea an d the eunucoid habit and a 46, XX or 46, XY karyotype without chromosomal abnormalities. It can be associated with complications such as osteoporosis and metabolic syndrome, increasing cardiovascular risk. We present a female patient of 16 years and 8 months of age who attended endocrinology clinic for presenting primary amenorrea.

Perrault syndrome with neurological features in a compound heterozygote for two TWNK mutations: overlap of TWNK-related recessive disorders.

BACKGROUND: Perrault syndrome is a rare autosomal recessive disorder that is characterized by the association of sensorineural hearing impairment and ovarian dysgenesis in females, whereas males have only hearing impairment. In some cases, patients present with a diversity of neurological signs. To date, mutations in six genes are known to cause Perrault syndrome, but they do not explain all clinically-diagnosed cases. In addition, the number of reported cases and the spectra of mutations are still small to establish conclusive genotype-phenotype correlations. METHODS: Affected siblings from family SH19, who presented with features that were suggestive of Perrault syndrome, were subjected to audiological, neurological and gynecological examination. The genetic study included genotyping and haplotype analysis for microsatellite markers close to the genes involved in Perrault syndrome, whole-exome sequencing, and Sanger sequencing of the coding region of the TWNK gene. RESULTS: Three siblings from family SH19 shared similar clinical features: childhood-onset bilateral sensorineural hearing impairment, which progressed to profound deafness in the second decade of life; neurological signs (spinocerebellar ataxia, polyneuropathy), with onset in the fourth decade of life in the two females and at age 20 years in the male; gonadal dysfunction with early cessation of menses in the two females. The genetic study revealed two compound heterozygous pathogenic mutations in the TWNK gene in the three affected subjects: c.85C>T (p.Arg29*), previously reported in a case of hepatocerebral syndrome; and a novel missense mutation, c.1886C>T (p.Ser629Phe). Mutations segregated in the family according to an autosomal recessive inheritance pattern. CONCLUSIONS: Our results further illustrate the utility of genetic testing as a tool to confirm a tentative clinical diagnosis of Perrault syndrome. Studies on genotype-phenotype correlation from the hitherto reported cases indicate that patients with Perrault syndrome caused by TWNK mutations will manifest neurological signs in adulthood. Molecular and clinical characterization of novel cases of recessive disorders caused by TWNK mutations is strongly needed to get further insight into the genotype-phenotype correlations of a phenotypic continuum encompassing Perrault syndrome, infantile-onset spinocerebellar ataxia, and hepatocerebral syndrome.

Biallelic mutations in LARS2 can cause Perrault syndrome type 2 with neurologic symptoms.

Perrault syndrome represents a genetically heterogeneous disorder characterized by sensorineural hearing loss in males and females and ovarian dysfunction in females. Causative genes include HARS2, HSD17B4, CLPP, C10orf2, and LARS2. Some patients with Perrault syndrome exhibit neurologic features including learning disability, cerebellar ataxia, and peripheral neuropathy and are classified as type 2 and are clinically separate from those without neurological symptoms other than a hearing loss (type 1). To date, all reported patients with LARS2 mutations (15 patients in 8 families) have been classified as type 1. Here, we report female siblings with biallelic mutations in LARS2, p.Glu294Lys, and p.Thr519Met, who were classified as type 2. The proposita developed progressive sensorineural hearing loss at 18 months and pervasive developmental disorder at 8 years, with repetitive behavior, insistence on sameness, attention deficit, tic, irritability, and an ataxic gait. At age 15 years, she was diagnosed as having primary amenorrhea with elevated FSH and LH and a decreased estradiol; ultrasound and magnetic resonance imaging examinations revealed a small uterus and no detectable ovaries. The proposita's younger sister presented with neonatal sensorineural hearing loss and a mild delay in motor and speech development. She was diagnosed as having primary amenorrhea with endocrinologic and radiographic findings that were comparable to those of her sister. She had difficulty with reading comprehension, and had trouble with open-ended test questions at 12 years of age. We concluded that Perrault syndrome patients with LARS2 mutations are at risk for neurologic problems, despite previous notions otherwise.

Marfanoid habitus is a nonspecific feature of Perrault syndrome.

The objective of this study was to report the clinical and biological characteristics of two Perrault syndrome cases in a Moroccan family with homozygous variant c.1565C>A in the LARS2 gene and to establish genotype-phenotype correlation of patients with the same mutation by review of the literature. Whole-exome sequencing was performed. Data analysis was carried out and confirmed by Sanger sequencing and segregation. The affected siblings were diagnosed as having Perrault syndrome with sensorineural hearing loss at low frequencies; the female proband had primary amenorrhea and ovarian dysgenesis. Both affected individuals had a marfanoid habitus and no neurological features. Both patients carried the homozygous variant c.1565C>A; p.Thr522Asn in exon 13 of the LARS2 gene. This variant has already been reported as a homozygous variant in three other Perrault syndrome families. Both affected siblings of a Moroccan consanguineous family with LARS2 variants had low-frequency sensorineural hearing loss, marfanoid habitus, and primary ovarian insufficiency in the affected girl. According to the literature, this variant, c.1565C>A; p.Thr522Asn, can be correlated with low-frequency hearing loss. However, marfanoid habitus was been considered a nonspecific feature in Perrault syndrome, but we believe that it may be more specific than considered previously. This diagnosis allowed us to provide appropriate management to the patients and to provide more accurate genetic counseling to this family.

Diagnóstico prenatal de síndrome de 'De la Chapelle' / Antenatal diagnosis of 'De la Chapelle' syndrome

Introducción: diagnóstico de las alteraciones morfológicas e histológicas y sus consecuencias postnatales que conlleva el diagnóstico intraútero del síndrome de De la Chapelle. Caso clínico: seguimiento gestacional de un caso de síndrome de De la Chapelle diagnosticado intraútero en ecografía morfológica. Se diagnostica de traslación génica en cariotipo mostrando las alteraciones evidentes al síndrome. Discusión: el diagnóstico intraútero precoz del síndrome de De la Chapelle constituye un hallazgo de gran valía en el tratamiento posterior de sus complicaciones (AU)

Background: To describe the morphological and histological alterations and postnatal consequences involved in an intrauterine diagnosis of De la Chapelle syndrome. Case report: Follow-up of a case of gestational De la Chapelle syndrome diagnosed on the basis of morphological ultrasound images. We diagnosed genetic translational alterations in the karyotype, revealing the syndrome. Discussion: Early intrauterine diagnosis of De la Chapelle syndrome is extremely useful in the subsequent treatment of its complications (AU)

Perrault syndrome with growth hormone deficiency: a rare autosomal recessive disorder.

Perrault syndrome is a rare genetically heterogeneous autosomal recessive group of disorders described in 1951 by Perrault as gonadal dysgenesis with deafness. Here we present a rare case of sporadic Perrault syndrome with short stature and growth hormone deficiency (GHD). Although there was a report on partial GHD in Perrault, our case is a first of its kind with documented GHD (Nishi Y, Hamamoto K, Kajiyama M, Kawamura I. The Perrault syndrome: clinical report and review. Am J Med Genet 1988;31:623-9). We report this case because of the rarity of keeping this condition as a differential diagnosis while evaluating for short stature with amenorrhea.

Mutations in Twinkle primase-helicase cause Perrault syndrome with neurologic features.

OBJECTIVE: To identify the genetic cause in 2 families of progressive ataxia, axonal neuropathy, hyporeflexia, and abnormal eye movements, accompanied by progressive hearing loss and ovarian dysgenesis, with a clinical diagnosis of Perrault syndrome. METHODS: Whole-exome sequencing was performed to identify causative mutations in the 2 affected sisters in each family. Family 1 is of Japanese ancestry, and family 2 is of European ancestry. RESULTS: In family 1, affected individuals were compound heterozygous for chromosome 10 open reading frame 2 (C10orf2) p.Arg391His and p.Asn585Ser. In family 2, affected individuals were compound heterozygous for C10orf2 p.Trp441Gly and p.Val507Ile. C10orf2 encodes Twinkle, a primase-helicase essential for replication of mitochondrial DNA. Conservation and structural modeling support the causality of the mutations. Twinkle is known also to harbor multiple mutations, nearly all missenses, leading to dominant progressive external ophthalmoplegia type 3 and to recessive mitochondrial DNA depletion syndrome 7, also known as infantile-onset spinocerebellar ataxia. CONCLUSIONS: Our study identifies Twinkle mutations as a cause of Perrault syndrome accompanied by neurologic features and expands the phenotypic spectrum of recessive disease caused by mutations in Twinkle. The phenotypic heterogeneity of conditions caused by Twinkle mutations and the genetic heterogeneity of Perrault syndrome call for genomic definition of these disorders.

Mutations in LARS2, encoding mitochondrial leucyl-tRNA synthetase, lead to premature ovarian failure and hearing loss in Perrault syndrome.

The genetic causes of premature ovarian failure (POF) are highly heterogeneous, and causative mutations have been identified in more than ten genes so far. In two families affected by POF accompanied by hearing loss (together, these symptoms compose Perrault syndrome), exome sequencing revealed mutations in LARS2, encoding mitochondrial leucyl-tRNA synthetase: homozygous c.1565C>A (p.Thr522Asn) in a consanguineous Palestinian family and compound heterozygous c.1077delT and c.1886C>T (p.Thr629Met) in a nonconsanguineous Slovenian family. LARS2 c.1077delT leads to a frameshift at codon 360 of the 901 residue protein. LARS2 p.Thr522Asn occurs in the LARS2 catalytic domain at a site conserved from bacteria through mammals. LARS2 p.Thr629Met occurs in the LARS2 leucine-specific domain, which is adjacent to a catalytic loop critical in all species but for which primary sequence is not well conserved. A recently developed method of detecting remote homologies revealed threonine at this site in consensus sequences derived from multiple-species alignments seeded by human and E. coli residues at this region. Yeast complementation indicated that LARS2 c.1077delT is nonfunctional and that LARS2 p.Thr522Asn is partially functional. LARS2 p.Thr629Met was functional in this assay but might be insufficient as a heterozygote with the fully nonfunctional LARS2 c.1077delT allele. A known C. elegans strain with the protein-truncating alteration LARS-2 p.Trp247Ter was confirmed to be sterile. After HARS2, LARS2 is the second gene encoding mitochondrial tRNA synthetase to be found to harbor mutations leading to Perrault syndrome, further supporting a critical role for mitochondria in the maintenance of ovarian function and hearing.

Hernia uteri inguinalis in a case of ovotesticular disorder of sexual differentiation.

An 18-year-old phenotypic male presented with an irreducible left inguinal mass, gynecomastia, and hypospadias. This mass on exploration was found to be a nonfunctional uterus with ipsilateral ovary and was excised. Further investigation confirmed the presence of a contralateral testis and a genotype of 46, XX. This confirmed the diagnosis of ovotesticular disorder of sexual differentiation (formerly true hermaphroditism) with obstructed hernia uteri inguinalis. The patient was raised as a male. Subcutaneous mastectomy for gynecomastia and neourethra construction with full thickness skin graft for hypospadias were performed. Hernia uteri inguinalis is rarely seen in this condition with only 2 cases being reported worldwide thus far, including our case.

Successful pregnancy outcome following gamete intra-Fallopian transfer in a patient with Müllerian dysgenesis.

A 29-year-old lady with Müllerian dysgenesis was keen to have a baby. Clinically, she was medium built with well-developed secondary female sexual characteristics. There was a short and blind vagina. She had undergone surgery for an imperforated hymen. Her FSH and LH concentrations were normal. Laparoscopy revealed a patent right Fallopian tube, a rudimentary right uterus and extensive pelvic endometriosis. She subsequently underwent gamete intra-Fallopian transfer (GIFT). Oocyte retrieval was carried out laparoscopically and a total of nine oocytes were retrieved. Four of the oocytes were transferred together with motile spermatozoa into the right Fallopian tube and the remaining five oocytes were inseminated with spermatozoa for IVF. Three embryos resulted and were frozen. She subsequently developed moderate ovarian hyperstimulation syndrome. Serum ß-human chorionic gonadotrophin concentration 14 days after GIFT was 1612 IU/l. Her antenatal care was relatively uneventful until 31 weeks of gestation when she was diagnosed to have intrauterine growth retardation and oligohydramnios. She then underwent an emergency Caesarean section at 32 weeks of pregnancy delivering a normal baby. This case study describes a successful pregnancy outcome following gamete intra-Fallopian transfer (GIFT) in a woman with malformation of the vagina (Müllerian dysgenesis). A 29-year-old lady with Müllerian dysgenesis diagnosed at 16 years of age was keen to become pregnant. Upon examination, a decision was made for a William's vulvovaginoplasty but as the patient was indecisive the surgery was deferred. Clinically, she is a medium-built lady with well-developed secondary female sexual characteristics. There was a short and blind vagina. Her serum FSH and LH concentrations were normal. Laparoscopy revealed a patent right Fallopian tube, a rudimentary right uterus and extensive pelvic endometriosis. She subsequently underwent GIFT. Nine oocytes were retrieved through laparoscopy. Four of the oocytes were transferred together with motile sperm into the right Fallopian tube and the remaining five oocytes were inseminated with sperm for IVF. Three embryos resulted and were frozen. Serum ß human chorionic gonadotrophin concentration measured 14 days after GIFT was 1612 IU/l. An abdominal ultrasonography performed at 5 weeks showed one intrauterine gestational sac. Her antenatal care was uneventful until 31 weeks of gestation when she developed a deficiency of amniotic fluid in the amniotic sac. She then underwent an emergency Caesarean section at 32 weeks of pregnancy. She delivered a healthy, normal 1.24 kg baby boy. Her post-natal care was uneventful.

Approach to assigning gender in 46,XX congenital adrenal hyperplasia with male external genitalia: replacing dogmatism with pragmatism.

The goal of sex assignment is to facilitate the best possible quality of life for the patient. Factors such as reproductive system development, sexual identity, sexual function, and fertility are important considerations in this regard. Although some DSD gender assignments are relatively straightforward, those with midstage genital ambiguity and unclear gonadal function represent a major challenge. A recent major change in DSD care has been to encourage a male assignment for 46,XY infants with ambiguous genitalia who have evidence of testicular function and in utero central nervous system androgen exposure. In contrast, assignment of virilized 46,XX DSD patients remains female when ovaries and internal organs are present, regardless of the extent of virilization of the external genitalia. In this paper, we propose consideration of male assignment for these 46,XX patients who have fully developed male genitalia based on available outcome data.

Laparoscopic surgery in 46,XX disorder of sex development: hysterosalpingectomy with gonadectomy.

PURPOSE: We present the outcomes of one of the largest series specifically of laparoscopic hysterosalpingectomy with bilateral gonadectomy in 46,XX patients with congenital adrenal hyperplasia raised as a male. PATIENTS AND METHODS: From June 2005 to March 2008, five patients raised as male were treated at our institution using laparoscopic surgery. 46,XX disorder of sex development was diagnosed in all the patients because of congenital adrenal hyperplasia. Hysterosalpingectomy with bilateral gonadectomy was performed completely laparoscopically in all five patients. RESULTS: All procedures were completed with minimal blood loss. The duration of the surgeries was 70-125 minutes. There were no complications during surgery or conversion to open surgery. The hospital stay ranged from 1 to 2 days, except in one patient who presented urinary retention and was discharged from the hospital a week after the surgery. CONCLUSIONS: Laparoscopic surgery can be safely used as part of the diagnosis and treatment of 46,XX disorder of sex development. Laparoscopy can be useful in the diagnosis as well as surgical management of Müllerian structures as well as intraabdominal gonads contrary to social sex.

47,XXX/45,X/46,XX mosaicism in a patient with Turner phenotype and spontaneous puberal development.

OBJECTIVE: To describe a patient with infertility and phenotypic combination of Turner and triple-X syndrome related to mos 47,XXX/45X/46,XX karyotype. DESIGN: Case report. SETTING: División de Genética, Centro de Investigación Biomédica de Occidente and Hospital de Ginecología y Obstetricia, CMNO, Instituto Mexicano del Seguro Social. PATIENT(S): The 24-year-old patient presented a phenotypic combination of Turner syndrome and X polysomy. She showed wide and short neck, low posterior hairline, cubitus valgus, bilateral shortening of the fourth and fifth metacarpals, multiple nevi, and müllerian anomalies but had spontaneous pubarche, thelarche, and menarche. INTERVENTION(S): Laboratory evaluations, imaging studies, ovarian biopsy, G-banding karyotype, and in situ fluorescence hybridization. MAIN OUTCOME MEASURE(S): Clinical and laboratory findings. RESULT(S): A karyotype: mos 47,XXX/45X/46,XX was found in the cytogenetic studies, a bicornuate uterus in the ultrasonographic scan, and a normal ovarian profile in the laboratory tests. CONCLUSION(S): The infertility in the present case can be related to either bicornuate uterus or subclinical abortions due to aneuploid ova. Cytogenetic assessment provides important information regarding infertile patients with uterine factors and short stature.

Follicle-stimulating hormone does not directly regulate bone mass in human beings: evidence from nature.

OBJECTIVE: To evaluate the effect of FSH levels in the development of human osteoporosis. DESIGN: Case-series study. SETTING: Gynecology department in a teaching hospital. PATIENT(S): A total of 8 women diagnosed with Kallman syndrome (KS) were compared with 11 with Turner syndrome and 11 with pure gonadal dysgenesia (GD, karyotype 46,XX). INTERVENTION(S): We assessed the pituitary-gonadal axis, bone turnover markers, bone mass, and patient characteristics. MAIN OUTCOME MEASURE(S): Bone mineral density as assessed by dual-energy X-ray absorptiometry, plasma FSH, LH, E(2), osteocalcin (BGP), and urinary type I collagen cross-linked N-telopeptide. Other biochemical markers included 25-hydroxyvitamin D, as well as parathyroid hormone and urine concentration of calcium and creatinine. RESULT(S): In girls with Turner syndrome and GD, FSH (64.03 +/- 29.2 and 90.08 +/- 22.41 mIU/mL, respectively) and LH (45.29 +/- 11.90 and 48.83 +/- 12.44 mIU/mL, respectively) levels were significantly higher compared with those observed in girls with KS (FSH: 1.87 +/- 0.64 and LH: 1.02 +/- 0.57), whereas no differences were detected in E(2) or bone marker levels. Bone mineral density correlated positively with FSH levels but not with E(2); however, after adjusting for previous growth-hormone therapy, these differences were not found. In addition, bone mineral density in spine and total hip was significantly lower in patients with KS. CONCLUSION(S): Follicle-stimulating hormone does not appear to have a major role in the development of bone loss in young women with primary amenorrhea.