Acute Encephalopathy in a 10-Year-Old Patient With Maple Syrup Urine Disease: A Challenging Diagnosis.

Maple syrup urine disease (MSUD) is a rare autosomal recessive metabolic disorder characterized by a deficiency in the branched-chain alpha-keto acid dehydrogenase complex, leading to the toxic accumulation of leucine, isoleucine and valine. Acute encephalopathy (AE) is a severe neurological disorder with diverse etiologies, demanding prompt identification and intervention. We present a unique case of a previously healthy teenage patient who developed AE during an influenza infection. Despite initial inconclusive investigations, the patient's condition rapidly deteriorated, requiring pediatric intensive care unit (PICU) admission. Diagnostic challenges included fluctuating mental status and refractory intracranial hypertension, ultimately necessitating decompressive craniectomy. Empirical treatments, including corticosteroids, tocilizumab, and plasmapheresis, were administered. Finally, clinical exome analysis revealed a pathogenic variant in homozygosity in the BCKDHA gene associated with MSUD type Ia. Her adult sister, experiencing similar symptoms in the same time period, did not survive. This case underscores the importance of considering metabolic disorders in AE etiology, even accounting for its various associated syndromes and usual prolonged diagnostic investigation, as prompt treatment initiation is vital for improved outcomes. Management of AE involves addressing seizures, systemic support and neuromonitoring, namely, intracranial pressure monitoring. Inborn errors of metabolism, like MSUD, should be considered, even if universally screened, as delayed diagnosis can result in prolonged hospitalization and significant morbidity.

Ocular severe involvement in oculofaciocardiodental syndrome: Description of a case series.

BACKGROUND: Oculofaciocardiodental (OFCD) syndrome is a rare genetic disorder affecting ocular, facial, dental, and cardiac systems, being an X-linked condition caused by pathogenic variants in the BCL-6 corepressor gene (BCOR). We report a case series of three female patients with OFCD syndrome with severe glaucoma. RESULTS: Three female patients with OFCD syndrome with different variants involving BCOR gene, in heterozygosity: a seven-years-old girl with an insertion (c.2037_2038dupCT), a nine years-old girl with a microdeletion in the X (p21.2-p11.4)) spanning the BCOR gene; and a 25 years-old female with a deletion (c.3858_3859del). Systemic involvement is variable among patients ranging from one patient mainly with ocular and dental involvement to one with associated intra-auricular and intra-ventricular defects. All the patients presented with congenital cataracts diagnosed in the first days of life. Cataract surgery was performed without incidents between 6 and 16 weeks of age in all the patients. Postoperatively, the three patients developed ocular hypertension and glaucoma with the need for surgical interventions, including trabeculectomy, Ahmed valve implantation, and cyclophotocoagulation. CONCLUSION: OFCD syndrome characterizes by a severe ocular involvement with glaucoma as a characteristic feature. Ocular hypertension after cataract surgery in these patients is challenging, almost always needing surgery during childhood. Therefore, we consider BCOR disruption may predispose to a higher incidence of glaucoma due to its aggressiveness and early onset on our case series. The awareness of these complications is crucial to an adequate follow-up of the patients.

Distinctive Amplitude-Integrated EEG Ictal Pattern and Targeted Therapy with Carbamazepine in KCNQ2 and KCNQ3 Neonatal Epilepsy: A Case Series.

BACKGROUND: Carbamazepine (CBZ) is effective in treating KCNQ2/3-related seizures, which may present with a distinctive amplitude-integrated electroencephalography (aEEG) pattern. OBJECTIVE: To assess how improved recognition of the distinctive aEEG ictal pattern associated with KCNQ2/3 variants has enabled early and effective targeted therapy with CBZ. METHODS: Retrospective descriptive study of five neonates with KCNQ2/3 pathogenic gene variants admitted at a level 3 neonatal intensive care unit (NICU) over an 8-year period. RESULTS: The distinctive ictal aEEG pattern was recognized in four neonates after an average of 61.5 hours (minimum 12 hours, maximum 120 hours) from the first electroclinical seizure and prompted the use of CBZ that was effective in all. The two most recently diagnosed patients could avoid polytherapy as they received CBZ as the first and second antiseizure medication, respectively. Three out of five patients with continuous normal voltage (CNV), sleep-wake cycling (SWC), and shorter postictal suppression had normal neurodevelopmental outcome. Regarding the remaining two infants, one was not trialed with CBZ and had a high seizure burden, both presented with a prolonged postictal suppression, no SWC, and had moderate-to-severe developmental delay. Genetic results became available after the neonatal period in all but one of the infants, who had a prenatal diagnosis. CONCLUSION: Recognition of the distinctive ictal aEEG pattern in the NICU allowed early and effective targeted therapy with CBZ in four neonates, well before genetic results became available. Furthermore, a CNV background pattern with SWC and short postictal suppression were associated with normal developmental outcomes.

Copy number variations on chromosome 2: impact on human phenotype, a cross-sectional study.

Background: Copy number variations (CNVs) on chromosome 2 are associated with a variety of human diseases particularly neurodevelopmental disorders. Array comparative genomic hybridization (aCGH) constitutes an added value for the diagnosis of neurodevelopmental or neuropsychiatric diseases. This study aims to establish a genotype-phenotype correlation, reporting CNVs on the chromosome 2, contributing for a better characterization of the molecular significance of rare CNVs in this chromosome. Methods: To accomplish this, a cross-sectional study was performed using genetic information included in a database of the Department of Genetics of the Faculty of Medicine and clinical data from Hospital database. CNVs were classified as pathogenic, benign, variants of unknown significance, and likely pathogenic or likely benign, in accordance with the ACMG Standards and Guidelines. Results: A total of 2897 patients were studied using aCGH, 32 with CNVs on chromosome 2, 24 classified as likely pathogenic, and 8 as pathogenic. Genomic intervals with a higher incidence were one 2p25.3 and 2q13 regions. Conclusions: This study will help to establish new genotype-phenotype correlations, allowing update of databases and literature and the improvement of diagnosis and genetic counseling which could be an added value for prenatal genetic counseling.

Expanding the genetic spectrum of ALKU syndrome: Compound heterozygosity for two deleterious variants in SMG8 gene.

Alzahrani-Kuwahara syndrome (ALKUS) is a neurodevelopmental disorder that includes microcephaly, facial dysmorphism, and variable congenital and eye malformations. We present the first case of ALKUS described in the European population caused by two variants in compound heterozygosity of the gene SMG8. We present a patient with two variants in compound heterozygosity in the SMG8 gene identified by in trio whole exome sequencing based in next generation sequencing (xGEN® Exome Research Panel, Nextseq550 platform). International case reporting (CARE) criteria were followed. Patient written consent was obtained through legal responsible persons. We describe a 27-year-old male, the second child of a healthy and non-consanguineous couple, whose genetic analysis showed two variants in compound heterozygosity, c.1159C > T (p.Arg387*) and c.2407del (p.Arg803Glyfs*10), in the SMG8 gene, both classified as likely pathogenic. As described by Fatema Alzahrani et al. in a series of eight patients, our patient had global developmental delay with impaired intellectual development, facial dysmorphism, and limb disproportion. Additionally, our patient had lower limb spastic paraparesis, marked osteotendinous hyperreflexia with extensor plantar response bilaterally and paretic gait. Our patient resembles the phenotype described by Fatema Alzahrani et al., however, he is the first patient with two SMG8 deleterious variants in compound heterozygosity, and the first to exhibit pyramidal signs and gait disorder as part of the phenotype.

Touraine-Solente-Gole syndrome: pathogenic variant in SLCO2A1 presented with polyarthralgia and digital clubbing.

BACKGROUND: Primary Hypertrophic Osteoarthropathy (PHO), also known as Touraine-Solente-Gole Syndrome, is a rare, multisystemic autosomal recessive disorder caused by pathogenic variants in the 15-hydroxyprostaglandin dehydrogenase (HPGD) or Solute Carrier Organic Anion Transporter Family Member 2A1 (SLCO2A1) genes. However, autosomal dominant transmission has also been described in some families with incomplete penetrance. PHO usually starts in childhood or adolescence, presenting with digital clubbing, osteoarthropathy, and pachydermia. We described a complete form of the syndrome in a male patient with a homozygous variant in the SLCO2A1 gene (c.1259G > T). CASE PRESENTATION: A 20-year-old male was referred to our Pediatric Rheumatology Clinic with a five-year history of painful and swollen hands, knees, ankles and feet, prolonged morning stiffness and relief with non-steroidal antiinflammatory drugs. He also reported late onset facial acne and palmoplantar hyperhidrosis. Family history was irrelevant and parents were non-consanguineous. On clinical examination, he presented clubbing of the fingers and toes, moderate acne and marked facial skin thickening with prominent scalp folds. He had hand, knee, ankles and feet swelling. Laboratory investigations showed elevated inflammatory markers. Complete blood count, renal and hepatic function, bone biochemistry were normal, as well as immunological panel. Plain radiographs revealed soft tissue swelling, periosteal ossification and cortical thickening of the skull, phalanges, femur and toe acroosteolysis. Due to the absence of other clinical signs suggesting a secondary cause, we suspected PHO. A genetic study revealed a likely pathogenic variant, c.1259G > T(p.Cys420Phe), in homozygosity in the SLCO2A1 gene, thus confirming the diagnosis. The patient started oral naproxen with significant clinical improvement. CONCLUSIONS: PHO should be kept in the differential diagnosis of inflammatory arthritis affecting children, often misdiagnosed as Juvenile Idiopathic Arthritis (JIA). To the best of our knowledge, this is the second genetically confirmed case of PHO in a Portuguese patient (first variant c.644 C > T), both made at our department.

Two Siblings With Recurrent Fevers: The Path to Mevalonate Kinase Deficiency Diagnosis.

Systemic autoinflammatory diseases (SAIDs) are a group of disorders that constitute a rare cause of recurrent fevers. Recurrent fevers are defined as periodic febrile episodes lasting from days to weeks, separated by symptom-free intervals of variable duration. They present multiple etiologies, representing a diagnostic challenge. Mevalonate kinase deficiency (MKD) is a genetic SAID, a rare hereditary recurrent fever syndrome (HRF) caused by pathogenic variants in the mevalonate kinase (MVK) gene. It is characterized by the early onset of periodic fever flares, frequently associated with joint, gastrointestinal, skin, and lymph node involvement. Although elevated serum immunoglobulin D (IgD) levels were previously considered an MKD's hallmark, normal values do not exclude it. High serum immunoglobulin A (IgA) is frequent. An acute-phase response and elevated urinary mevalonic acid (UAV) excretion during flares may aid in the diagnosis. Genetic testing is an essential tool to confirm the diagnosis. The authors report two siblings presenting with early infancy onset of recurrent febrile illness and characteristic associated symptoms, one of which was initially misdiagnosed with periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome. MKD diagnoses were only established at 12 and nine years old, respectively, after the identification of the same two MVKgene variants. The diagnosis in the eldest favored the earlier recognition of MKD in the youngest. Owing to its wide spectrum of manifestations, with many being nonspecific and/or shared with other more frequent entities, a significant proportion of MKD patients present a long delay until its final establishment. These cases illustrate the MKD diagnosis and management's difficulties, reinforcing the importance of a careful clinical history and HRF awareness for its prompt diagnosis and appropriate precocious referral.

Novel Arthrogryposis Multiplex Congenita Presentation in a Newborn With Pierpont Syndrome.

Pierpont syndrome is a rare and recently described multiple congenital anomaly syndrome, classically characterized by global developmental delay, distinctive facial dysmorphic features, and abnormal fat distribution in distal limbs. Only few cases were previously documented. We report a case of a term male neonate admitted to the neonatal intensive care unit because of feeding difficulties. Intrauterine growth restriction, microcephaly, and bilateral equinovarus foot were diagnosed in the second trimester, and prenatal array comparative genomic hybridization showed no abnormality. Physical examination revealed bilateral flexion deformities of wrists, elbows, knees and clubfoot, large hands and feet, deep palmar and plantar grooves, and calcaneo-plantar fat pads. Craniofacial dysmorphism, axial hypotonia, and hypoactivity were also observed. Due to the presence of congenital and non-progressive joint contractures, arthrogryposis multiplex congenita (AMC) was considered. A comprehensive diagnostic workup, including a Next Generation Sequencing target panel, was performed but did not establish a diagnosis. The clinical exome identified an heterozygous pathogenic variant in the TBL1XR1 gene (NM_001321194.1: c.1337A>G, p.[Tyr446Cys]), allowing Pierpont syndrome diagnosis. Our case stands out for reporting the novel AMC presentation in a Pierpont syndrome newborn. The broader and precocious genetic testing proved to be an essential clarifying diagnostic tool. Our patient supports the relation between the p.Tyr446Cys sequence variant in TBL1XR1 gene with this rare syndrome, reinforcing its association with a distinctive and recognizable phenotype, as well as expanding its clinical features to include AMC.

Prenatal diagnosis study using array comparative genomic hybridization for genotype-phenotype correlation in 772 fetuses.

OBJECTIVE: The aim was to evaluate the main indications for prenatal diagnosis, the prevalence of abnormal copy number variations (CNVs), correlate them with clinical findings, analyze the prevalence of VUS, report the rare variants found and additionally highlight the clinical importance of microarray-based comparative genomic hybridization (aCGH) in prenatal diagnosis. STUDY DESIGN: We retrospectively analyzed a cohort of 772 fetuses with indication for genetic study in two tertiary hospitals, in a 9-years-period, using aCGH. RESULTS: Our results demonstrated 8.3 % (6.4-10.5 %, 95 % CI) detection rate of pathogenic CNVs. Within this group, the main indication was structural malformations (57 %) mainly involving central nervous system, skeletal and cardiac systems. Pathogenic results in cases with multiple malformations were higher than in cases with isolated anatomical system malformations showing statistical significant differences (p < 0.001). The second indication where we found more pathogenic CNVs was increased nuchal translucency (5-6.4 mm). In fact, the rate of pathogenic CNVs did not show significant differences between structural and non-structural malformations (p > 0.001), highlighting the relevance of genetic study by aCGH also in cases with no structural malformations. A total of 217 fetuses with CNVs classified as VUS were identified, mainly involving chromosomes X, 1 and 16. CONCLUSION: Our findings demonstrate 4.9 % (4.2-5.6 %, 95 % CI) increased in the diagnostic yield using aCGH compared to the use of conventional karyotype alone, confirming that the aCGH can improve the accuracy of prenatal diagnosis. Our survey provides a full genotype-phenotype analysis that can be clinically useful for the classification of variants in the context of prenatal setting, helping to provide a better reproductive genetic counselling.

Cat-Eye Syndrome: A Report of Two Cases and Literature Review.

Cat-eye syndrome is a rare genetic disease that involves the proximal long (q) arm of chromosome 22. The classic clinical triad includes coloboma of the iris, ears, and anal malformations. This syndrome was named "cat eye" due to the vertical coloboma of the iris. However, the spectrum of clinical manifestations is variable, and the iris coloboma may be absent in 40-50% of cases. Association with congenital heart disease is also frequent and its diagnosis should raise suspicion of a genetic condition. We describe two cases of male infants affected by the cat-eye syndrome, of which no one presented the classic clinical triad. One of them had unpredictable complications that led to prolonged neonatal intensive care unit stay. Although having distinct phenotypes, the diagnosis in both cases was made through nonobstructive total anomalous pulmonary venous return, anal imperforation, and craniofacial anomalies. Iris coloboma was an important clue only in one of them. Prenatal diagnosis is a challenge, such that a genetic study is essential for a final diagnosis in the absence of the classic triad.

Clinical Findings on Chromosome 1 Copy Number Variations.

Copy number variants (CNVs) are a major contribution to genome variability, and the presence of CNVs on chromosome 1 is a known cause of morbidity. The main objective of this study was to contribute to chromosome 1 disease map, through the analysis of patients with chromosome 1 CNVs.A cross-sectional study was performed using the array comparative genomic hybridization database of the Genetic Department of the Faculty of Medicine. Patients with pathogenic (P) or likely pathogenic (LP) CNVs on chromosome 1 were selected for the study. Clinical information was collected for all patients. Databases and related literature were used for genotype-phenotype correlation.From a total of 2,516 patients included in the database we identified 24 patients (0.95%) with P (9 patients) or LP (15 patients) CNVs on chromosome 1. These CNVs account for 6.1% (24/392 CNVs) of the total P/LP CNVs in the database. Most common CNVs found were in the 1q21.1-1q21.2 region.This study reinforces the association between chromosome 1 CNV and neurodevelopmental disorders and craniofacial dysmorphisms. Additionally, it also strengthened the idea that CNVs interpretation is not always a linear task due to the broad spectrum of variants that can be identified between benign and clearly pathogenic CNVs.

Congenital myopathies in adults: A diagnosis not to overlook.

BACKGROUND: Congenital myopathies (CM) were traditionally classified according to the muscle histopathological features, but in recent years, molecular diagnosis has become increasingly important. CM may present a wide phenotype variability, and while adult-onset CM have been increasingly recognized, substantial diagnostic delays are still reported. OBJECTIVES: To describe a cohort of adult CM patients, including clinical, genetic, and histopathological features, and further characterize the subgroup of adult-diagnosed patients. MATERIALS AND METHODS: We performed a retrospective observational cohort study to characterize the CM patients evaluated in our adult Neuromuscular outpatient clinic, including the subgroup of adult-diagnosed patients. RESULTS: We identified 19 CM patients with compatible molecular and/or histological diagnoses, of which 14 were diagnosed in adulthood. Eleven adult-diagnosed patients had symptoms since childhood and 9 had a family history of myopathy. The median age of symptoms' onset was 4 years old and the median age at diagnosis was 37 years old. The most common causative gene was RYR1, followed by TTN and MYH7. Three patients had non-specific features on muscle biopsy, all diagnosed during adulthood. CONCLUSIONS: In our cohort, the majority of CM were diagnosed in adulthood, despite most having pediatric-onset symptoms and positive family history. The diagnostic delay may be associated with mild presentation, slow course, atypical muscle histology, and lack of awareness of adult-onset CM. Studies with larger populations are needed.

Cone dystrophy with supernormal rod responses: A rare KCNV2 gene variant.

PURPOSE: To describe the clinical, electrophysiological, and genetic findings of three Portuguese families with a rare variant in the KCNV2 gene resulting in "cone dystrophy with supernormal rod responses" (CDSRR). METHODS: Retrospective clinical revision of five individuals from three unrelated families with CDSRR. Ophthalmological examination was described in all patients and included color vision testing, fundus photography, fundus autofluorescence (FAF) imaging, spectral domain-optical coherence tomography (SD-OCT), pattern electroretinogram (ERG), and full-field ERG. The mutational screening of the KCNV2 gene was performed with Sanger and Next Generation Sequencing. RESULTS: All patients showed childhood-onset photophobia and progressive visual acuity loss with varying degrees of severity. In multimodal imaging, various degrees of retinal pigment epithelium disturbances and outer retinal atrophy, which tend to be worst with advancing age, were observed. Molecular screening identified a rare presumed truncating variant (p.Glu209Ter) in homozygosity in two families and in compound heterozygosity in a third family. Three patients showed ERG changes characteristic of CDSRR, however, two patients presented with incomplete electrophysiological features of the disease. CONCLUSION: A rare variant in the KCNV2 gene was identified in five patients from three Portuguese families. This variant often leads to a severe and progressive form of retinopathy. Considerable variability in the ERG responses among patients with this KCNV2 variant was observed.

Two Novel Disease-Causing Variants in the PDE6C Gene Underlying Achromatopsia.

We report the clinical phenotype and genetic findings of two variants in PDE6C underlying achromatopsia (ACHM). Four patients with the variant c.1670G>A in exon 13 of the PDE6C gene were identified. Additionally, one had compound heterozygous genotype, with two variants in the PDE6C gene, a variant of c.2192G>A in exon 18 and c.1670G>A in exon 13. All patients presented the symptomatic triad of decreased visual acuity, severe photophobia, and colour vision disturbances. SD-OCT showed an absence of the ellipsoid zone, creating an optically empty cavity at the fovea in three patients. The patient with the compound heterozygous genotype presented a more severe subfoveal outer retina atrophy. ERG recordings showed extinguished responses under photopic and 30-Hz flicker stimulation, with a normal rod response. We identified two new variants in the PDE6C gene that leads to ACHM.

Tricorhinophalangeal Syndrome type 1: a novel variant and Perthes-like hip changes as first manifestation.

We report a case of Trichorhinophalangeal syndrome type I (TRPS1) in a 16-year-old boy who was referred due to painless finger deformities over the last year. Legg-Calvé-Perthes disease (LGP) had been diagnosed at age 7 and required surgical treatment at age 12. Parents were healthy and non consanguineous; there was family history of pectus carinatum of maternal lineage. On examination the patient presented a bulbous nose, thin and sparse scalp hair; pectus carinatum; clinodactyly of the first and fifth fingers and hard painless swelling of all of the proximal interphalangeal joints; brachydactyly of the toes. Laboratory tests were unremarkable and radiographic studies revealed distinctive abnormalities of the hands (e.g., epiphyseal coning). This diagnosis was confirmed by gene sequencing, which identified in heterozygosity a pathogenic variant c.124G>T (p.Glu42Ter) in the exon 3 of the TRPS1 gene. The diagnosis of TRPS1 may be suspected upon identification of characteristic physical features, a compatible clinical history and imaging findings.

A novel homozygous frameshift variant in the cellular retinaldehyde-binding protein 1 (RLBP1) gene causes retinitis punctata albescens.

BACKGROUND: Retinitis punctata albescens is a form of retinitis pigmentosa characterized by white fleck-like deposits in the fundus, in most cases caused by pathogenic variants in RLBP1 gene. The purpose of this work is to report the phenotypic and genotypic data of a patient with retinitis punctata albescens carrying a deletion in the RLBP1 gene. RESULTS: An 8-year-old Caucasian female has been complaining of nyctalopia for the last 2 years. No other ocular symptoms were present. No relevant past medical or familiar history was described. At clinical examination, the patient's best-corrected visual acuity was 20/20 in both eyes. Anterior segment evaluation and intraocular pressure were normal in both eyes. At fundoscopy, multiple punctate whitish-yellow fleck-like lesions were observed in the proximity of temporal superior and inferior vascular arcades. Scotopic electroretinogram demonstrated severely reduced rod response, without improvement or recovery of rod system function after prolonged dark adaptation. Blood DNA samples of this patient and from her parents were screened for causal variants in RLBP1, RDH5, and PRPH2. CONCLUSION: A probable pathogenic frameshift variant was identified in homozygosity in the RLBP1 gene with an autosomal recessive transmission as another cause of retinitis punctata albescens. This DNA variant will aid ongoing functional studies and add to our understanding of the molecular pathology about RLBP1-associated retinopathies.

A novel MFRP gene variant in a family with posterior microphthalmos, retinitis pigmentosa, foveoschisis, and foveal hypoplasia.

BACKGROUND: To characterize the phenotype and genotype of a syndrome associating posterior microphthalmos (PM), retinitis pigmentosa (RP), foveoschisis, and foveal hypoplasia (FH) in a consanguineous Portuguese family. MATERIALS AND METHODS: Three siblings were studied and underwent comprehensive eye examinations for best-corrected visual acuity, axial length, refractive error, B-mode ultrasound, electroretinography, retinography, fluorescein angiography (FA), kinetic visual field (VF), and optical coherence tomography (OCT). Molecular analysis was performed by Sanger sequencing of the entire coding region of the MFRP gene. RESULTS: All members presented nyctalopia, decreased visual acuity, and constriction of the VF, as well as bilateral shortening of the posterior ocular segment and normal anterior segment dimensions. The fundoscopy and ERG results were compatible with RP. Macular OCT analysis revealed schisis of the outer retinal layer, FH, as well as retinal and choroidal folds. We identified a homozygous mutation in intron 9 of the membrane frizzled-related protein (MFRP) gene (c.1124 + 1 G > A). CONCLUSIONS: Our study shows a family with PM and RP due to a mutation in the MFRP gene. The relationship has previously been proven, but this specific mutation has never been described. These gene mutations show wide phenotypic variability, being evident in the presence of foveoschisis, retinal and choroidal folds, and FH, other than PM and RP.

Wiedemann-Steiner syndrome in two patients from Portugal.

Wiedemann-Steiner syndrome (WSS) is a rare genetic disorder characterized by growth retardation, facial dysmorphism, hypertrichosis cubiti and neurodevelopment delay. It is caused by pathogenic variants in the KMT2A gene. This report describes two unrelated Portuguese patients, age 11 and 17 years, with a phenotype concordant with WSS and clinical and molecular diagnosis of WSS by the identification of two novel frameshift variants in the KMT2A gene. This work also highlights the presence of certain clinical features in patients with growth retardation and development delay and should draw attention to the diagnosis of WSS, when hirsutism, particularly hypertrichosis cubiti is present.