Phenotypes, Genetics, and Estimated Prevalence of Focal Dermal Hypoplasia (Goltz Syndrome): A Single-Center Report.

BACKGROUND: Focal dermal hypoplasia (FDH), also known as Goltz syndrome, is a rare ectodermal dysplasia that primarily affects the skin, skeleton, and eyes. It is an X-linked dominant disorder, predominantly seen in females, caused by pathogenic variants in PORCN. METHODS: We characterized a case series of four genetically confirmed FDH patients (three females, one male) at Aarhus University Hospital, Denmark. We estimated the FDH prevalence from our local cohort and nationwide registry data. RESULTS: Three patients had characteristic dermatological findings suspicious for FDH and confirmed by targeted PORCN analysis. One patient had an atypical presentation with several malformations but only subtle skin changes and was diagnosed following trio exome-sequencing analysis. Skin atrophy with fat herniations and telangiectasias were typical cutaneous findings. Limb malformations included oligodactyly (cleft foot), syndactyly, and polydactyly. Eye abnormalities included coloboma and microphthalmos. Facial dysmorphology was defined by asymmetry, thin upper lip, and malformed ears. One patient developed a giant cell bone tumor, which is a rare feature of FDH. Dental findings included enamel hypoplasia with vertical grooving and irregular crowns. Four PORCN variants were identified, including three not previously reported in the literature.We estimated a regional point prevalence in Western Denmark of 1.6 cases per million population (95% confidence intervals (CI): 0.7-3.7 per million) and a nationwide registry-based point prevalence of 1.2 cases per million population (95% CI: 0.6-2.4 per million). CONCLUSIONS: FDH is an extremely rare and complex multisystem disorder of variable presentation, which requires close multidisciplinary collaboration for diagnosis and patient care.

Clinical presentation and genetics of tricho-rhino-phalangeal syndrome (TRPS) type 1: A single-center case series of 15 patients and seven novel TRPS1 variants.

Tricho-rhino-phalangeal syndrome (TRPS) is a rare malformation syndrome characterized by distinctive facial, ectodermal, and skeletal features. TRPS is divided into TRPS type I/III caused by pathogenic variants in TRPS1 and TRPS type II caused by contiguous gene deletions also spanning EXT1 and RAD21. Due to its rarity, knowledge of the clinical course of TRPS remains limited. Therefore, we collected and characterized a case series of 15 TRPS type I patients (median age at diagnosis 15 [interquartile range: 10-18] years, 11 females [73%]) seen at Aarhus University Hospital, Denmark, with a median follow-up period of 10 years. We estimated a minimum point prevalence of 0.5 in 100,000 (95% CI: 0.3-0.8 per 100,000) persons. Common craniofacial features included fine and sparse hair with a high anterior hairline, eyebrows with lateral thinning and a thicker medial part, prominent ears, a bulbous nose tip with small nasal alae, a low-hanging, and often wide columella, and a long philtrum with a thin upper vermillion. Specific skeletal features included short stature and deviating and short fingers with cone-shaped epiphyses and shortened metacarpals on radiographs. The most significant morbidity of the cohort was joint complaints, which were reported by all patients, often already before the TRPS diagnosis was established. We identified ten different TRPS1 variants including both frameshift/nonsense, missense, and splice-site variants, including seven variants not previously reported in the literature. In accordance with previous literature, no genotype-phenotype correlation was identified. The clinical trajectories were heterogeneous involving pediatrics, dermatology, orthopedic surgery, clinical genetics, and/or odontology, emphasizing that close multidisciplinary collaboration is essential for early diagnosis of TRPS and to ensure proper and timely patient care and counseling.

Autosomal recessive Noonan-like syndrome caused by homozygosity for a previously unreported variant in SPRED2.

Noonan syndrome is characterized by variable phenotypic expressivity with characteristic dysmorphic facial features, varying degrees of intellectual disability, developmental delay, short stature, and congenital heart defects in 50-80%. Other findings include a webbed neck, cryptorchidism, coagulation defects and eye abnormalities. Thus far, Noonan syndrome has mainly been attributed to heterozygous pathogenic variants in 10+ different genes, with the rare exception of cases due to biallelic pathogenic variants in LZTR1. Recently, homozygous loss-of-function variants in SPRED2 have been identified as a cause of a recessive Noonan syndrome-like phenotype. We present the phenotypes of two additional patients with homozygosity for a previously unreported loss-of-function variant in SPRED2, thereby adding relevant clinical information about the recently described Noonan syndrome-like SPRED2-related phenotype.

Incidence of Aicardi-Goutières syndrome and KCNT1-related epilepsy in Denmark.

Objective: To estimate the incidence of Aicardi-Goutières syndrome (AGS) and potassium sodium-activated channel subfamily T member 1 (KCNT1)-related epilepsy in Denmark and to characterize the patients diagnosed with AGS and KCNT1-related epilepsy. Background: AGS and KCNT1-related epilepsy are 2 distinct rare genetic disorders. Due to the rarity of AGS and KCNT1-related epilepsy, the epidemiology remains unclear. The incidences for these diseases or the carriers with disease-related genetic variants remain unknown. Materials and methods: This is a retrospective, non-interventional, population-based study using aggregate data from the Danish population register and hospital-based patient-level data in Denmark to identify persons with genetically confirmed AGS between January 2010 to December 2020 and KCNT1-related epilepsies between January 2012 to December 2020. Cases of these disorders were identified from in-hospital databases, and pathogenic variants were identified and confirmed by Sanger and/or whole exome (panel-based) sequencing. The incidence of AGS and KCNT1-related epilepsy were estimated in separate statistical analyses. Results: A total of 7 AGS patients were identified. The mean age at AGS diagnosis was 19.4 months (median age 14 months). TREX1 (n < 5) and RNASEH2B (n ≥ 5) genes were reported with confirmed pathogenic variants. The birth incidence of AGS was <0.7600 per 100,000 live births. The average annual incidence rate was calculated as 0.0539 (95% CI: 0.0217-0.1111) per 100,000 persons per year in the total population < 18 years (n = 7); the average annual incidence rate was <0.7538 per 100,000 persons per year (n < 5) in the population < 12 months, and the average annual incidence rate in the population ≥ 12 months and < 18 years was <0.0406 per 100,000 persons per year (n < 5). A total of 14 KCNT1-related epilepsy cases were identified during the study period (n = 5 in 2016, remaining 9 cases in 2013 and 2015). The mean age at diagnosis was 20.6 years (median 19 years) for KCNT1 cases. A total of 8 cases (57.1%) were ≥ 18 years, and 6 (42.9%) were < 18 years at diagnosis. The phenotype autosomal dominant or sporadic sleep-related hypermotor epilepsy (ADSHE) (n = 10, 71.4%) was most reported; the remaining 4 cases had either epilepsy of infancy with migrating focal seizures (EIMFS) or an unclassifiable developmental and epileptic encephalopathy (DEE). The birth incidence of KCNT1-related epilepsy was ≤1.1205 per 100,000 live births. The average annual incidence rates per 100,000 persons per year during the study period were 0.0431 (95% confidence interval [CI]: 0.0236-0.0723; n = 14) in the overall population ≤ 50 years, 0.0568 (95% CI: 0.0209-0.1237; n = 6) in the population < 18 years, and 0.0365 (95% CI: 0.0157-0.0718; n = 8) in the population ≥ 18 and ≤ 50 years. There were 3 families with at least 2 cases diagnosed with KCNT1-related epilepsies (on average 3.3 cases per family), indicating 10 cases in total within the 3 families. All KCNT1 cases of ADSHE phenotype came from the 3 families. The higher incidence of older ages and ADSHE cases compared with previous KCNT1 studies is likely due to the capture of prevalent and familial previously undiagnosed cases. Excluding these family cases, the average annual incidence was 0.0123 (95% CI: 0.0034-0.0315, n = 4) per 100,000 persons per year in the population ≤ 50 years during 2012-2020. Conclusions: AGS and KCNT1-related epilepsy are particularly rare diseases. The annual average incidence rate of AGS was 0.0539 per 100,000 persons per year in the population < 18 years and birth incidence was <0.7600 per 100,000 live births during 2010-2020. The average annual incidence rate of KCNT1-related epilepsy was 0.0431 per 100,000 persons per year in the population ≤ 50 years and the birth incidence was ≤1.1205 per 100,000 live births during 2012-2020. Given similar healthcare systems and genetic pools, these findings may provide insight on the incidence of these rare diseases in the Nordics.

Managing CLN2 disease: a treatable neurodegenerative condition among other treatable early childhood epilepsies.

INTRODUCTION: Neuronal ceroid lipofuscinosis type 2 (CLN2 disease) is a rare pediatric neurodegenerative condition, which is usually fatal by mid-adolescence. Seizures are one of the most common early symptoms of CLN2 disease, but patients often experience language deficits, movement disorders, and behavioral problems. Diagnosis of CLN2 disease is challenging (particularly when differentiating between early-onset developmental, metabolic, or epileptic syndromes), and diagnostic delays often overlap with rapid disease progression. An enzyme replacement therapy (cerliponase alfa) is now available, adding CLN2 disease to the list of potentially treatable disorders requiring a prompt diagnosis. AREAS COVERED: Although advances in enzymatic activity testing and genetic testing have facilitated diagnoses of CLN2 disease, our review highlights the presenting symptoms that are vital in directing clinicians to perform appropriate tests or seek expert opinion. We also describe common diagnostic challenges and some potential misdiagnoses that may occur during differential diagnosis. EXPERT OPINION: An awareness of CLN2 disease as a potentially treatable disorder and increased understanding of the key presenting symptoms can support selection of appropriate tests and prompt diagnosis. The available enzyme replacement therapy heralds an even greater imperative for early diagnosis, and for clinicians to direct patients to appropriate diagnostic pathways.

[Diagnosis, monitoring and treatment of tuberous sclerosis complex].

Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder with highly varying disease manifestations, many of which cause extensive morbidity. There are international consensus criteria for the diagnosis, monitoring and treatment of TSC, and approved medical treatment for some of the most serious disease manifestations. However, organisation of a rational and coordinated care of TSC patients involves many different medical specialities and is only sparsely described. This review describes the interdisciplinary care of TSC patients at Aarhus University Hospital, Denmark.