Researching Waardenburg syndrome (WS) underscores its rarity and complex symptomatology, presenting as a congenital disorder predominantly inherited in an autosomal dominant pattern. It exhibits incomplete penetrance, which results in a wide range of clinical manifestations, with variable phenotypic presentations within the same family as well. The most commonly found features are facial abnormalities, hypopigmentation of the skin, heterochromia iridis, and conductive deafness. Adding to the eccentricities of this syndrome are its four subtypes, each presenting with its specific clinical features, which helps in delineating the subtype. A mutated paired box 3 (PAX3​​​​​) gene manifests as type 1 Waardenburg, which is characterized by sideways displacement of the inner angles of the eyes (i.e., dystopia canthorum), widely spaced eyes, congenital sensorineural hearing impairment, and patchy pigmentation of the iris, skin, and hair. Due to insufficient research, it has been difficult to isolate all the genetic mutations responsible for type 2, but its phenotype is very similar to type 1 with minor differences. Type 3 is characterized by musculoskeletal abnormalities. Waardenburg-Shah syndrome (type 4), which is associated with Hirschsprung disease, is the rarest subtype and is caused by genetic mutations in the endothelin receptor type B (EDNRB), endothelin-3 (EDN3), or sex-determining region Y (SRY) box 10 (SOX10) gene. We present a case series of this unique subtype that presented with a typical history of constipation due to Hirschsprung disease and had phenotypic manifestations of white forelock, heterochromia iridis, and bilateral sensorineural hearing loss (SNHL). In parallel with a positive 1° family history of a white forelock, we reflect on the fundamentals of this unique syndrome, as well as its management protocols, highlighting the importance of genetic counseling and cultivation of a high index of suspicion for its diagnosis.

BACKGROUND: Familial adenomatous polyposis (FAP) is an inherited disorder. At present, an increasing number of medications are being employed to treat FAP; however, only a few have been assessed for their efficacy and safety. Therefore, this study aimed to conduct a network meta-analysis to compare the therapeutic outcomes and adverse drug reactions of all FAP-associated medications.
METHODS: Six relevant databases were searched to identify pertinent randomized controlled trials (RCTs), and information on the dosage and frequency of various drugs was extracted. Additionally, data on changes in polyp counts and dimensions, as well as treatment-related adverse reactions for different medications were collected. The Bayesian method was employed to directly or indirectly compare the impact of different treatment regimens on changes in polyp numbers and diameters, and the safety of the drugs was investigated.
RESULTS: CXB at 16 mg/kg/day significantly reduced polyp numbers. Celecoxib at 8 mg/kg/day and sulindac (150 mg twice daily) plus erlotinib (75 mg/day) were effective for tolerant FAP patients. Additionally, EPAFFA 2 g daily and sulindac (150 mg twice daily) plus erlotinib (75 mg/day) emerged as the most effective for reducing polyp size.
CONCLUSIONS: The most effective treatment for reducing the number of colorectal polyps is celecoxib 16 mg/kg/day. On the other hand, a daily dosage of 2 g EPA-FFA demonstrates the best results in terms of decreasing colorectal polyp diameter.

Oro-facial-digital syndrome, specifically Mohr syndrome, is an uncommon genetic disorder characterized by predominant oro-facial anomalies and polysyndactyly. While typically associated with autosomal recessive and X-linked dominant inheritance patterns, this case presents an autosomal dominant mode of transmission. This report documents the clinical presentation of three individuals, a 12-year-old male child and two females, 10-year-old and eight-year-old, who have inherited the disorder from their ancestors. The observed features include post-axial polysyndactyly in both upper and lower limbs, with the male child exhibiting additional manifestations of strabismus and knee joint defects. Symptomatic management is pursued due to the absence of complications, with surgical interventions and subsequent cosmetic repairs planned for all three children. Post-surgical physiotherapy is scheduled as part of their comprehensive treatment plan. The prognosis for this disorder is generally favorable, with a complete recovery anticipated and no complications expected.

Thyroid hormone resistance (THR) is a rare inherited disorder that affects approximately one in every 40,000 live births. This condition arises from a mutation in the thyroid hormone receptor β, leading to reduced responsiveness of target tissues. It can result in a combination of hypothyroidism and hyperthyroidism symptoms in different tissues. The thyroid hormone is crucial for controlling blood pressure, and even small changes in its levels can have an effect on vascular resistance, cardiac performance, and heart rhythm. Both hypo- and hyperthyroidism have been associated with elevated blood pressure, underscoring the significant link between thyroid hormone sensitivity and vascular function. Considering thyroid hormone sensitivity is essential in clinical practice, particularly when managing patients with hypertension, to ensure personalized and effective treatment approaches. Monitoring thyroid function is essential during the diagnosis of hypertension, as thyroid dysfunction can often be corrected to normalize blood pressure. It\'s crucial to distinguish between essential hypertension and hypertension associated with a thyroid abnormality in THR. The mechanisms behind the development of hypertension in THR include reduced nitric oxide production, dysregulation of the renin-angiotensin-aldosterone system, impaired endothelial function, and mutations in the deiodinases. Physicians should understand the underlying mechanisms of THR and identify new therapeutic targets for hypertension in THR.

Noonan syndrome with multiple lentigines (NSML, formerly known as LEOPARD syndrome) is a variant of Noonan syndrome which is an autosomal dominant disorder. Most cases of NSML are secondary to mutations of the protein-tyrosine phosphatase nonreceptor type 11 (PTPN11). Hypertrophic cardiomyopathy (HCM) remains the most frequent and serious cardiac abnormality in this inherited syndrome, and it may lead to sudden cardiac death related to HCM-associated outflow obstruction and fatal arrhythmia. Beyond cardiac involvement, NSML may present with multiple lentigines, ocular hypertelorism, genital anomalies, short stature and deafness. Herein, we report three patients with NSML among three generations in one family, all presenting with multiple lentigines, HCM and other distinctive clinical and molecular features, including facial dysmorphism, deafness, family history of sudden death and PTPN11 mutations. This case series highlights the importance of early echocardiography examinations for patients with NSML. Careful family screening and genetic counselling are also necessary, especially in patients with diffuse lentigines or a history of sudden death among family members. We also discuss the distinctive cardiac features and phenotypic characteristics at different stages of NSML, including childhood, adulthood and elderhood.

Whether or not conditions should be included in publicly funded newborn screening (NBS) programs should be discussed according to objective and transparent criteria. Certain criteria have been developed for the introduction of NBS programs in the context of individual countries; however, there are no standard selection criteria for NBS programs in Japan. This study aimed to develop a quantitative scoring model to assess newborn screening that incorporates the views of a variety of stakeholders in Japan. The five recommended eligibility criteria for NBS were stratified based on previous studies and expert opinions, using the analytic hierarchy process. We conducted a cross-sectional, web-based questionnaire targeting a wide range of people involved in NBS to investigate pairwise comparisons of the evaluation items between February and April of 2022. There were 143 respondents. Most of our respondents (44.1%) were physicians. Fifty-eight respondents (40.6%) had been engaged in NBS-related research or work for more than 10 years. The distribution of allocation points was the highest for \'intervention\', \'screening test\', \'follow-up setting\', \'economic evaluation\', and \'disease/condition\', in that order. The algorithm in this study will guide decision makers in collecting and evaluating objective data, thus enabling transparent discussions to occur.

UNASSIGNED: Neurofibromatosis type I is rarely associated with vascular abnormalities. Here, we report a case of rapid airway stenosis caused by a ruptured occipital artery that was treated with surgical airway management.
UNASSIGNED: A 40-year-old woman, with no medical history, presented with a chief complaint of a sudden neck pain on the left side. She had a prominent mass in the outer left side of the neck. After arrival at the emergency room, the patient complained of severe dyspnea and experienced a rapid drop in oxygen saturation. Supplemental ventilation was ineffective, and tracheal intubation was attempted; however, laryngeal expansion could not be observed because of the enlarged cervical mass. Therefore, to manage the surgical airway, a cricothyrotomy was first carried out, which resulted in an immediate increase in oxygen saturation. Two percutaneous embolizations and one surgical procedure were carried out, and the patient was discharged without any complications.
UNASSIGNED: For a sudden onset cervical mass, airway management should be undertaken, keeping in mind the possibility of worsening rapid airway narrowing due to bleeding.

Bietti crystalline dystrophy (BCD) is a rare, genetically determined chorioretinal dystrophy presenting with intraretinal crystalline deposits and varying degrees of progressive chorioretinal atrophy commencing at the posterior pole. In some cases, there can be concomitant corneal crystals noted first in the superior or inferior limbus. CYP4V2 gene, a member of the cytochrome P450 family is responsible for the disease and more than 100 mutations have been defined thus far. However, a genotype-phenotype correlation has not been established yet. Visual impairment commonly occurs between the second and third decades of life. By the fifth or sixth decade of life, vision loss can become so severe that the patient may potentially become legally blind. Multitudes of multimodal imaging modalities can be utilized to demonstrate the clinical features, course, and complications of the disease. This present review aims to reiterate the clinical features of BCD, update the clinical perspectives with the help of multimodal imaging techniques, and overview its genetic background with future therapeutic approaches.

Hypophosphatasia (HPP) is an inherited disease caused by mutation of the alkaline phosphatase (ALPL) gene in an autosomal dominant or an autosomal recessive manner. The main symptoms of HPP are bone hypomineralization and early exfoliation of the primary teeth. Some of the mutations identified in autosomal dominant families are reported to have dominant negative effects. In addition, the penetrance can vary among patients with the same variant even within the same family, resulting in various phenotypes of systemic symptoms. However, differences in dental symptoms between patients with HPP and carriers with the same ALPL variant have not been reported. Herein, we report on two sisters who had the same heterozygous ALPL variant with dominant negative effects. The older sister had bone and dental symptoms and was diagnosed with childhood HPP. In contrast, the younger sister was a carrier with no bone and dental symptoms. It can be inferred that this phenomenon was caused by the difference in penetrance. This case revealed that carriers with the ALPL mutation may have no dental symptoms characteristic of HPP. Because HPP is sometimes progressive, it is very important to carefully monitor carriers to detect the possible onset of dental and systemic symptoms.

Familial hypercholesterolemia (FH) is an inherited, autosomal dominant metabolic disorder mostly associated with disease-causing variant in LDLR, APOB or PCSK9. Although the dominant changes are small-scale missense, frameshift and splicing variants, approximately 10% of molecularly defined FH cases are due to copy number variations (CNVs). The first-line strategy is to identify possible pathogenic SNVs (single nucleotide variants) using multiple PCR, Sanger sequencing, or with more comprehensive approaches, such as NGS (next-generation sequencing), WES (whole-exome sequencing) or WGS (whole-genome sequencing). The gold standard for CNV detection in genetic diagnostics are MLPA (multiplex ligation-dependent amplification) or aCGH (array-based comparative genome hybridization). However, faster and simpler analyses are needed. Therefore, it has been proposed that NGS data can be searched to analyze CNV variants. The aim of the study was to identify novel CNV changes in FH patients without detected pathogenic SNVs using targeted sequencing and evaluation of CNV calling tool (DECoN) working on gene panel NGS data; the study also assesses its suitability as a screening step in genetic diagnostics. A group of 136 adult and child patients were recruited for the present study. The inclusion criteria comprised at least “possible FH” according to the Simon Broome diagnostic criteria in children and the DLCN (Dutch Lipid Clinical Network) criteria in adults. NGS analysis revealed potentially pathogenic SNVs in 57 patients. Thirty selected patients without a positive finding from NGS were subjected to MLPA analysis; ten of these revealed possibly pathogenic CNVs. Nine patients were found to harbor exons 4−8 duplication, two harbored exons 6−8 deletion and one demonstrated exon 9−10 deletion in LDLR. To test the DECoN program, the whole study group was referred for bioinformatic analysis. The DECoN program detected duplication of exons 4−8 in the LDLR gene in two patients, whose genetic analysis was stopped after the NGS step. The integration of the two methods proved to be particularly valuable in a five-year-old girl presenting with extreme hypercholesterolemia, with both a pathogenic missense variant (c.1747C>T) and exons 9−10 deletion in LDLR. This is the first report of a heterozygous deletion of exons 9 and 10 co-occurring with SNV. Our results suggest that the NGS-based approach has the potential to identify large-scale variation in the LDLR gene and could be further applied to extend CNV screening in other FH-related genes. Nevertheless, the outcomes from the bioinformatic approach still need to be confirmed by MLPA; hence, the latter remains the reference method for assessing CNV in FH patients.