Genomic sequencing highlights the diverse molecular causes of Perrault syndrome: a peroxisomal disorder (PEX6), metabolic disorders (CLPP, GGPS1), and mtDNA maintenance/translation disorders (LARS2, TFAM).

Perrault syndrome is a rare heterogeneous condition characterised by sensorineural hearing loss and premature ovarian insufficiency. Additional neuromuscular pathology is observed in some patients. There are six genes in which variants are known to cause Perrault syndrome; however, these explain only a minority of cases. We investigated the genetic cause of Perrault syndrome in seven affected individuals from five different families, successfully identifying the cause in four patients. This included previously reported and novel causative variants in known Perrault syndrome genes, CLPP and LARS2, involved in mitochondrial proteolysis and mitochondrial translation, respectively. For the first time, we show that pathogenic variants in PEX6 can present clinically as Perrault syndrome. PEX6 encodes a peroxisomal biogenesis factor, and we demonstrate evidence of peroxisomal dysfunction in patient serum. This study consolidates the clinical overlap between Perrault syndrome and peroxisomal disorders, and highlights the need to consider ovarian function in individuals with atypical/mild peroxisomal disorders. The remaining patients had variants in candidate genes such as TFAM, involved in mtDNA transcription, replication, and packaging, and GGPS1 involved in mevalonate/coenzyme Q10 biosynthesis and whose enzymatic product is required for mouse folliculogenesis. This genomic study highlights the diverse molecular landscape of this poorly understood syndrome.

A Case Series Study on Growth Hormone Therapy in Children with Prader-Willi Syndrome in Portugal.

INTRODUCTION: Prader-Willi syndrome is a multisystemic genetic disorder associated with shorter adult height. Nowadays, all paediatric Prader-Willi syndrome patients are considered for growth hormone treatment. We present the experience of this treatment at a Portuguese paediatric endocrinology unit and intend to emphasise the importance of creating a follow-up national network of these patients. MATERIAL AND METHODS: Longitudinal, retrospective, analytical study of Prader-Willis syndrome patients using data between 1989 and 2021. Growth hormone therapy was offered to eligible patients. The analysis included all Prader-Willis syndrome patients, with a comparison between treated and untreated patients; a longitudinal analysis of patients receiving growth hormone therapy (baseline, 12 and 36 months of follow-up) was also carried out. The statistical analysis was carried out using STATA® v13.0. RESULTS: Out of 38 patients with Prader-William syndrome, 61% were male. The median age at diagnosis was four months and 61% received growth hormone therapy. The patients who reached adulthood, or 18 years old, had a median near-adult height, Z-score of -2.71, and their median body mass index indicated class 2 obesity, regardless of growth hormone therapy. Patients had a lower body mass index in the growth hormone group (35 vs 51 kg/m2, p < 0.042) near-adult height. CONCLUSION: This case series represents the first national study that included patients on growth hormone therapy after the National Health Service started supporting the treatment for Prader-Willi syndrome patients and supports its use, reinforcing the positive effects on growth and body mass index. Longer follow-up studies are needed to analyse the effect of growth hormone on patient metabolic profiling, body composition and cognitive level.

Introdução: A síndrome de Prader-Willi é uma doença genética multissistémica associada a baixa estatura. Atualmente, todos os doentes pediátricos com síndrome de Prader-Willi são candidatos a terapia com hormona do crescimento. Apresentamos a experiência desta terapêutica numa unidade de Endocrinologia Pediátrica portuguesa e realçamos a importância de criar uma base de dados nacional de seguimento destes doentes. Material e Métodos: Estudo longitudinal, retrospetivo e analítico de doentes com síndrome de Prader-Willi utilizando dados entre 1989 e 2021. A terapia com hormona de crescimento foi administrada aos doentes elegíveis. Foi realizada análise de todos os doentes com síndrome de Prader-Willi, com comparação doentes tratados/não tratados; foi também realizada uma análise longitudinal dos doentes sob hormona de crescimento (início/12/36 meses de seguimento). O tratamento estatístico foi realizado com recurso ao STATA® v13.0. Resultados: De um total de 38 doentes com síndrome de Prader-Willi, 61% eram do sexo masculino. Idade média de diagnóstico quatro meses e 61% sob hormona de crescimento. Os doentes que atingiram a idade adulta apresentaram um Z-score de mediana de estatura alvo de -2,71, e índice de massa corporal obesidade nível 2, independentemente da terapêutica com hormona de crescimento. Os doentes apresentaram um índice de massa corporal menor no grupo tratado com hormona de crescimento (35 vs 51 kg/m2, p < 0,042). Conclusão: Este estudo de série de casos de doentes com síndrome de Prader-Willi tratados com hormona de crescimento é pioneiro a nível nacional desde a comparticipação deste tratamento pelo Sistema Nacional de Saúde português e apoia esta terapêutica, reforçando os seus efeitos positivos no crescimento e índice de massa corporal. Serão necessários estudos com seguimento mais prolongado para analisar o seu efeito no perfil metabólico, composição corporal e cognição.

Permanent neonatal diabetes mellitus due to KCNJ11 mutation in a Portuguese family: transition from insulin to oral sulfonylureas.

Permanent neonatal diabetes mellitus (PNDM) is a rare form of diabetes diagnosed within the first 6 months of life. Heterozygous activation mutations in KCNJ11, encoding the Kir6.2 subunit of the ATP-sensitive potassium (K(ATP)) channel, which acts as a key role in insulin secretion regulation, account for about half of the cases of PNDM. The majority of the patients represent isolated cases resulting from de novo mutations. Approximately 20% have associated neurologic features: the most severe form, which includes epilepsy and developmental delay, is called developmental delay, epilepsy, and neonatal diabetes (DEND) syndrome and the milder form, with less severe developmental delay and without epilepsy, is designated intermediate DEND syndrome. Individuals with KCNJ11 mutations have been successfully transitioned from insulin to sulfonylurea (SU) therapy. Furthermore, there have been cases reported with variable improvement in neurological function following a successful switching. We describe a 12-year-old Portuguese girl with PNDM due to the previously reported R201C mutation in the KCNJ11 gene. Her medical history includes prematurity and moderate developmental delay. The mutation was inherited from her mother who has isolated PNDM. The patient was successfully transferred from insulin to SU, whereas her mother showed SU resistance. Despite good glycemic control, no improvements in the cognitive performance were verified. We present our experience in switching treatment from insulin to oral SUs in this family, and also discuss whether or not the girl's developmental delay is related with the Kir6.2 mutation. To our knowledge, this is the first Portuguese patient reported with successful transition to SU treatment.

Face-sparing Congenital Generalized Lipodystrophy Type 1 Associated With Nonclassical Congenital Adrenal Hyperplasia.

CONTEXT: Congenital generalized lipodystrophy, type 1 (CGL1), due to biallelic pathogenic variants in AGPAT2, is characterized by the near total loss of body fat from the face, trunk, and extremities. Patients develop premature diabetes, hypertriglyceridemia, hepatic steatosis, and polycystic ovary syndrome. However, sparing of the facial fat and precocious pubertal development has not been previously reported in CGL1. CASE DESCRIPTION: We report a 21-year-old woman of European descent with CGL1 who had sparing of the facial fat and premature thelarche at birth with premature pubarche and menstrual bleeding at age 3 years. Her serum 17-OH progesterone level rose to 1000 ng/dL (30.26 nmol/L) after cosyntropin stimulation test, suggestive of nonclassical congenital adrenal hyperplasia (NCAH) due to 21-hydroxylase deficiency. Hydrocortisone replacement therapy from age 3.5 to 10 years resulted in cessation of menstruation and growth of pubic hair, and a reduction of breast size. Sanger and whole-exome sequencing revealed compound heterozygous variants c.493-1G>C; p.(Leu165_Gln196del), and c.del366_588+534; p.(Leu123Cysfs*55) in AGPAT2 plus c.806G>C; p.(Ser269Thr) and c.844G>T; p.(Val282Leu) in CYP21A2. She developed diabetes at age 13 requiring high-dose insulin and had 7 episodes of acute pancreatitis due to extreme hypertriglyceridemia in the next 5 years. Metreleptin therapy was initiated at age 18 and after 3 years, she had remission of diabetes and hypertriglyceridemia; however, menstrual irregularity and severe hirsutism did not improve. CONCLUSION: Concomitant NCAH in this CGL1 patient was associated with precocious pubertal development and sparing of facial fat. Metreleptin therapy drastically improved her hyperglycemia and hyperlipidemia but not menstrual irregularity and hirsutism.

Type 1 diabetes mellitus, hypothyroidism and celiac disease in a girl with Down's syndrome--a rare association.

The prevalence of comorbilities such as type 1 diabetes mellitus (DM1), celiac disease and hypothyroidism is higher in Down's syndrome (DS) compared with the general population; however, the association of all these pathologies is rare. We report a girl with DS, now 7 years old, who developed DM1, hypothyroidism and celiac disease at different times. The authors consider important that follow-up programs for patients with DS include screening for these pathologies.

CYP21A2 Gene Pathogenic Variants: A Multicenter Study on Genotype-Phenotype Correlation from a Portuguese Pediatric Cohort.

BACKGROUND: Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD) is an autosomal recessive disorder characterized by 3 overlapping phenotypes: salt-wasting (SW), simple virilizing (SV), and non-classic (NC). We aimed at conducting a nationwide genotype description of the CAH pediatric patients and to establish their genotype-phenotype correlation. METHODS: CAH patients were recruited from Portuguese pediatric endocrinology centers and classified as SW, SV, or NC. Genetic analysis was performed by polymerase chain reaction (sequence specific primer, restriction fragment length polymorphism) or direct Sanger sequencing. Genotypes were categorized into 4 groups (0, A, B, and C), according to their predicted enzymatic activity. In each group, the expected phenotype was compared to the observed phenotype to assess the genotype-phenotype correlation. RESULTS: Our cohort comprises 212 unrelated pediatric CAH patients (29% SW, 11% SV, 60% NC). The most common pathogenic variant was p.(Val282Leu; 41.3% of the 424 alleles analyzed). The p.(Val282Leu) variant, together with c.293-13A/C>G, p.(Ile173Asn), p.(Leu308Thr), p.(Gln319*), and large deletions/conversions were responsible for 86.4% of the mutated alleles. Patients' stratification by disease subtype revealed that the most frequent pathogenic variants were c.293-13A/C>G in SW (31.1%), p.(Ile173Asn) in SV (46.9%), and p.(Val282Leu) in NC (69.5%). The most common genotype was homozygosity for p.(Val282Leu; 33.0%). Moreover, we found 2 novel variants: p.(Ile161Thr) and p.(Trp202Arg), in exons 4 and 5, respectively. The global genotype-phenotype correlation was 92.4%. Group B (associated with the SV form) showed the lowest genotype-phenotype correlation (80%). CONCLUSION: Our cohort has one of the largest NC CAH pediatric populations described. We emphasize the high frequency of the p.(Val282Leu) variant and the very high genotype-phenotype correlation observed.

Adrenal Hypoplasia Congenita: A Rare Cause of Primary Adrenal Insufficiency and Hypogonadotropic Hypogonadism.

Primary adrenal insufficiency is defined by the impaired synthesis of adrenocortical hormones due to an intrinsic disease of the adrenal cortex. Determining its etiology is crucial to allow adequate long-term management and genetic counseling. We report the case of a male adolescent that presented in the neonatal period with adrenal crisis and received replacement therapy for primary adrenal insufficiency. During follow-up, adrenal hypoplasia congenita (AHC) was suspected given his persistently raised adrenocorticotropic hormone levels, with markedly low 17-OH progesterone and androstenedione levels. DNA sequence analysis revealed a mutation in NR0B1 gene (c.1292delG), confirming the diagnosis. Delayed puberty and persistent low levels of gonadotropins led to testosterone replacement therapy. X-linked AHC is a rare cause of primary adrenal insufficiency and hypogonadotropic hypogonadism, related to mutations in NR0B1 gene. Despite its rarity, AHC should be considered in patients who present with primary adrenal failure, low levels of 17-OH progesterone and hypogonadotropic hypogonadism.

[Growth and puberty in type 1 diabetes mellitus - experience from a pediatric endocrinology unit]. / Crescimento e puberdade na diabetes mellitus tipo 1 - experiência de uma unidade de endocrinologia pediátrica.

BACKGROUND: Type 1 Diabetes Mellitus (T1DM) is the most common endocrine-metabolic disease in children. It is associated with vascular and neuropathic complications, and may also affect growth and development. OBJECTIVE: To correlate the metabolic control and disease duration with growth and puberty in patients with T1DM followed in a Pediatric Endocrinology Outpatient Clinic. SUBJECTS AND METHODS: Retrospective analysis. Sample obtained from patients with T1DM followed in Hospital Santa Maria Pediatric Endocrinology Outpatient Clinic (Lisbon - Portugal) since 1994 until March 2011. INCLUSION CRITERIA: patients diagnosed before the onset of puberty and who had attained their final height during the follow-up. VARIABLES: sex, age, weight and height at diagnosis and final, parents' height, growth velocity, pubertal height gain, age at menarche and metabolic control during puberty. RESULTS: 39 patients, 51% female, 82% diagnosed less than five years before puberty. Fifty-four percent presented an average HbA1c between 8-10%, what we considered reasonable. There seems to be a trend towards an inverse association between HbA1c and the maximum speed of growth and pubertal height gain, although not statistically significant. These patients were taller than average at diagnosis (z-score: male 0.9; female: 0.5) and lost height during puberty, yet attained final heights within normal range and matching their target heights. CONCLUSIONS: Although HbA1c seems to negatively influence maximum growth rate and pubertal height gain, there was no compromise in final height in this group of patients.

Klinefelter's Syndrome: 18 years experience of a pediatric endocrinology unit / Síndrome de Klinefelter: 18 anos de experiência de uma unidade de endocrinologia pediátrica

Methods: A cross-sectional retrospective study was conducted, based on clinical data of patients diagnosed with Klinefelter Syndrome and followed from January 1992 to December 2009 (18 years) at a Pediatric Endocrinology Unit of a tertiary care-level hospital in Portugal.Results: In the study period 15 patients were identified. Seven had a positive prenatal diagnosis of Klinefelter Syndrome and eight had post-natal diagnosis, after investigation for psychomotor development delay, behavioral disruptions and/or suggestive phenotype (four of them only diagnosed during adolescence). Thirteen patients had a peripheral blood karyotype of 47, XXY and two presented 47, XXY/46, XY mosaicism. The median age of first visit was seven years. Onset of puberty occurred spontaneously in seven cases. Puberty induction was performed in three patients, at age of 14 years. Those who needed hormone treatment had an effective response with no side effects. Behavioral and social inadequacies were identified in two cases and moderate global motor developmental delay in nine. Hyperactivity and attention deficit disorder were diagnosed in five patients, currently treated with methylphenidate.Conclusions: A global motor development delay together with physical features of Klinefelter Syndrome in a child justifies karyotyping given the high prevalence of this syndrome, especially if socialization problems and learning difficulties are present. This study highlights the need for greater awareness in diagnosis as well as the importance of multidisciplinary approach in the care and education of these patients.

Objetivos: descrever as características clínicas de crianças e adolescentes com Síndrome de Klinefelter.Métodos: foi realizado um estudo transversal retrospectivo, com base em dados clínicos dos pacientes com diagnóstico de Síndrome de Klinefelter acompanhados entre janeiro de 1992 e dezembro de 2009 (18 anos) na Unidade de Endocrinologia Pediátrica de um hospital de cuidados terciários em Portugal.Resultados: foram identificados 15 pacientes no período do estudo. Sete tiveram diagnóstico positivo pré-natal de Síndrome de Klinefelter e oito tiveram o diagnóstico pós-natal, após investigação por atraso no desenvolvimento psicomotor, distúrbios comportamentais e / ou fenótipo sugestivo (quatro deles diagnosticados apenas durante a adolescência). Treze pacientes tinham um cariótipo de sangue periférico de 47, XXY e dois apresentaram 47, XXY/46, mosaicismo XY. A idade mediana da primeira visita foi de sete anos. Início da puberdade ocorreu espontaneamente em sete casos. Indução da puberdade foi realizada em três pacientes, com a idade de 14 anos. Aqueles que precisaram de tratamento hormonal tiveram uma resposta eficaz, sem efeitos colaterais. Inadequações comportamentais e sociais foram identificadas em dois casos e atraso moderado de desenvolvimento motor global em nove. Hiperatividade e transtorno de déficit de atenção foram diagnosticados em cinco pacientes, atualmente tratados com metilfenidato.Conclusões: atraso global do desenvolvimento, juntamente com características físicas da Síndrome de Klinefelter em uma criança, justifica a solicitação de cariótipo, dada a elevada prevalência dessa síndrome, especialmente se estiveram presentes problemas de socialização e dificuldades de aprendizagem. Este estudo destaca a necessidade de uma maior conscientização para o diagnóstico, bem como a importância da abordagem multidisciplinar no cuidado e na educação desses pacientes.