Battling a rarity: A case of kindler syndrome from a developing country.

Kindler syndrome, a rare branching of inherited epidermolysis bullosa, is an autosomal recessive condition characterized by the eruption of painful blisters and hemorrhagic vesicles in infancy. With age, the eruption of blisters are seen to decline leaving behind fibrosed, scarred, and paper-like skin, and poikilodermic features. To this date, about 400 cases have been reported worldwide for this disease only. This report aims to discuss the presence and diagnosis of Kindler Syndrome using limited resources in developing countries. It describes the presence of clinically diagnosed Kindler Syndrome in a young male of Pakistani descent that started in infancy and presented with a variety of clinical features over the years. Even though genetic analysis remains the gold standard diagnostic for Kindler syndrome, for third world countries, relying on Diagnostic clinical criteria remains helpful in establishing a diagnosis of Kindler syndrome for further management, as seen in our patient.

Defective monocyte plasticity and altered cAMP pathway characterize USB1-mutated poikiloderma with neutropenia Clericuzio type.

Poikiloderma with neutropenia (PN) Clericuzio type (OMIM #604173) is a rare disease with areas of skin hyper- and hypopigmentation caused by biallelic USB1 variants. The current study was spurred by poor healing of a perianal tear wound in one affected child homozygous for c.266-1G>A (p.E90Sfster8) mutation, from a family reported previously. Treatment with G-CSF/CSF3 or GM-CSF/CSF2 transiently increased neutrophil/monocytes count with no effect on wound healing. Analysis of peripheral blood revealed a lack of non-classical (CD14+/- CD16+ ) monocytes, associated with a systemic inflammatory cytokine profile, in the two affected brothers. Importantly, despite normal expression of cognate receptors, monocytes from PN patients did not respond to M-CSF or IL-34 in vitro, as determined by cytokine secretion or CD16 expression. RNAseq of monocytes showed 293 differentially expressed genes, including significant downregulation of GATA2, AKAP6 and PDE4DIP that are associated with leucocyte differentiation and cyclic adenosine monophosphate (cAMP) signalling. Notably, the plasma cAMP was significantly low in the PN patients. Our study revealed a novel association of PN with a lack of non-classical monocyte population. The defects in monocyte plasticity may contribute to disease manifestations in PN and a defective cAMP signalling may be the primary effect of the splicing errors caused by USB1 mutation.

Rothmund-Thomson syndrome, a disorder far from solved.

Rothmund-Thomson syndrome (RTS) is a rare autosomal recessive disorder characterized by a range of clinical symptoms, including poikiloderma, juvenile cataracts, short stature, sparse hair, eyebrows/eyelashes, nail dysplasia, and skeletal abnormalities. While classically associated with mutations in the RECQL4 gene, which encodes a DNA helicase involved in DNA replication and repair, three additional genes have been recently identified in RTS: ANAPC1, encoding a subunit of the APC/C complex; DNA2, which encodes a nuclease/helicase involved in DNA repair; and CRIPT, encoding a poorly characterized protein implicated in excitatory synapse formation and splicing. Here, we review the clinical spectrum of RTS patients, analyze the genetic basis of the disease, and discuss molecular functions of the affected genes, drawing some novel genotype-phenotype correlations and proposing avenues for future studies into this enigmatic disorder.

Kindler syndrome: a rare case report from Syria.

Kindler syndrome is a rare autosomal recessive inherited disease. The authors report a case with unique presentation that has never reported before in the medical Literatur" lanugo hair". This is a case of a 13-year-old Syrian child, who presented with difuse fine face hair, and serious urinary complications. Kindler syndrome is characterized by acral skin blistering beginning at birth, diffuse cutaneous atrophy, photosensitivity, poikiloderma, and various mucosal findings. Highlighting a set of clinical diagnostic criteria; which is used only if a genetic test is not available.

Kindler's Syndrome with Recurrent Neutropenia: Report of Two Cases from Saudi Arabia.

Kindler syndrome (KS) is a rare photosensitivity disorder with autosomal recessive mode of inheritance. It is characterized by acral blistering in infancy and childhood, progressive poikiloderma, skin atrophy, abnormal photosensitivity, and gingival fragility. Besides these major features, many minor presentations have also been reported in the literature. We are reporting two cases with atypical features of the syndrome and a new feature of recurrent neutropenia. Whole exome sequencing analysis was done using next-generation sequencing which detected a homozygous loss-of-function (LOF) variant of FERMT1 in both patients. The variant is classified as a pathogenic variant as per the American College of Medical Genetics and Genomics guidelines. Homozygous LOF variants of FERMT1 are a common mechanism of KS and as such confirm the diagnosis of KS in our patients even though the presentation was atypical.

Hereditary fibrosing poikiloderma (POIKTMP syndrome) report of a new mutation and review of the literature.

Hereditary fibrosing poikiloderma with tendon contractures, myopathy, and pulmonary fibrosis (POIKTMP) is a genodermatosis with autosomal dominant inheritance caused by mutations in FAM111B. We report another case with a new pathogenic variant and analyze all previously published 34 cases with a focus on sequence of clinical presentation and genotype-phenotype correlation. POIKTMP is characterized by marked age-dependent clinical expressivity. FAM111B encodes a catalytic nuclear protein, expressed in many tissues, which contributes to impaired DNA repair affecting multiple systems. Specific inhibition of catalytic activity might be a future strategy to halt progression of this otherwise untreatable disease. Given the relentless progression of the disease, it would make sense to start such treatment as early as possible. In order to achieve this objective, children with suspected POIKTMP should therefore undergo early imaging of all relevant organ systems.

Precocious puberty and anal stenosis in an African patient with Rothmund-Thomson syndrome.

Rothmund-Thomson syndrome (RTS) is a rare autosomal recessive disorder characterized by a rash that progresses to poikiloderma. Other common features include sparse hair, eyelashes and eyebrows, short stature, variable skeletal abnormalities, dental defects, cataracts, hypogonadism, and an increased risk for cancer, especially osteosarcoma and skin cancer. RTS is caused by biallelic pathogenic variants in ANAPC1 (Type 1 RTS) or RECQL4 (Type 2 RTS). We present an African girl with Type 2 RTS caused by a nonsense variant and an intronic variant in RECQL4. The patient presented precocious puberty, which has not been previously reported in RTS and that was treated with a GnRH analog, and anal stenosis, which has only been reported once. This case highlights the need to consider deep intronic variants in patients with RTS when pathogenic variants in the coding regions and exon/intron boundaries are not identified and expands the phenotypic spectrum of this disorder.

Juvenile Dermatomyositis Presenting As Generalized Poikiloderma: A Case Report.

Juvenile dermatomyositis (JDM) is a chronic autoimmune inflammatory disorder and is considered the most common form of idiopathic inflammatory myopathies. JDM primarily affects the skin and the skeletal muscles. Characteristic signs and symptoms include Gottron papules, heliotrope rash, calcinosis cutis, and symmetrical proximal muscle weakness. However, JDM presenting with generalized scaly poikeloderma is an unfamiliar presentation. Herein we report a 14-month-old female toddler presented with generalized progressive asymptomatic scaly mottled violaceous patches (poikilodermatous) that started when she was seven months old. Her lab results were unremarkable. She was diagnosed with poikilodermatous skin rash with a differential diagnosis of Amyopathic dermatomyositis, poikilodermatous genodermatosis, and patch-stage mycosis fungoides. She was prescribed moisturizer creams only. A year later, during a follow-up, she presented with a full picture of JDM, with a history of scaly poikilodermatous skin patches that became more widespread, frequent choking during oral intake, and not being able to stand and sit unsupported. Laboratory workup was significant for low WBC and hemoglobin counts, along with elevated CPK, LDH, ferritin, CRP, and ESR levels. MRI revealed the right anterior thigh and vastus lateralis subcutaneous edema. Therefore, the child was diagnosed and treated as a case of JDM.

Case Report: Diverse phenotypes of congenital poikiloderma associated with FAM111B mutations in codon 628: A case report and literature review.

Congenital poikiloderma is an extremely rare autosomal dominant genetic syndrome, characterized by a combination of early onset poikiloderma, telangiectasia, and epidermal atrophy. FAM111B gene with multiple mutations has been identified as a potential causative gene for congenital poikiloderma. In this report, we described a boy with congenital poikiloderma confirmed by clinical manifestations. Next-generation sequencing based on a gene probe panel consisting of 541 genetic loci of genodermatoses, was used to screen mutations of the proband and his parents. Results showed that a missense mutation in the FAM111B gene c.1883G>A (rs587777238) was identified in the proband, but absent in his parents, indicating the mutation is de novo. In conclusion, a new case of congenital poikiloderma in China was reported, and the hotspot mutations in codon 628 of FAM111B gene was reviewed, as well as authenticating the uncertain association between genotypes and phenotypes in this rare disease.

Expanding phenotype of FAM111B-related disease focusing on liver involvement: Literature review, report of a case with end-stage liver disease and proposal for a new acronym.

POIKiloderma, tendon contractures, myopathy, pulmonary fibrosis is a congenital multisystem disorder due to FAM111B dominant variants. We present a literature review focusing on the frequency and the impact of hepatic involvement and a case report of a patient with severe end-stage liver disease. Whole exome sequencing (WES) was conducted on the proband and his parents. A de novo FAM111B: c.1879A > G; (p.Arg627Gly) variant was identified. Hepatic involvement is present in 11 out of the 30 patients described in the literature, with different levels of dysfunction ranging from mild transaminitis to liver fibrosis found in three different cases by liver biopsies. Liver involvement seems to be a significant cause of morbidity. We propose to modify the previous acronym in POIK-TMPL: including POIKiloderma, tendon contractures, myopathy, pulmonary fibrosis/pancreas insufficiency and cancer, liver involvement/lymphedema. Moreover, we suggest screening patients with FAM111B variants for liver involvement from the first month of life and continue with an appropriate follow-up. Further studies are needed to better understand this frequent complication.

Xeroderma pigmentosum: an updated review.

Background: Early recognition of xeroderma pigmentosum is important to minimize the complications arising from the harmful effects of exposure to ultraviolet radiation. This narrative review aims to familiarize physicians with the clinical features, diagnosis and management of xeroderma pigmentosum. Methods: A search was conducted in December 2021 in PubMed Clinical Queries using the key term "xeroderma pigmentosum". The search strategy included all clinical trials, observational studies and reviews published within the past 10 years. The information retrieved from the search was used in the compilation of this article. Results: Xeroderma pigmentosum is a condition of abnormal DNA repair of ultraviolet radiation-induced and oxidative DNA damage, which leads to increased skin cancer susceptibility. Approximately 50% of patients with xeroderma pigmentosum have increased photosensitivity and certain types of xeroderma pigmentosum are more prone to ocular disease and progressive neurodegeneration depending on the causative mutation. The diagnosis should be suspected in patients with increased photosensitivity and characteristic cutaneous, ophthalmological and neurological findings. A definite diagnosis can be made by the identification of biallelic mutation in one of the causative genes. Strict and consistent sun avoidance and protection and early detection and treatment of premalignant and malignant skin lesions are the mainstays of management. Treatment options for actinic keratosis include cryotherapy, topical imiquimod, topical 5-fluorouracil, chemical peeling, excision, CO2 laser resurfacing, fractional/pulsed laser therapy, and photodynamic therapy. Cutaneous malignancy can be treated by photodynamic therapy, curettage and electrodesiccation, or surgical excision. Oral isotretinoin, oral niacinamide, topical imiquimod and topical fluorouracil can be used for the prevention of skin malignancy. Treatment options for poikiloderma include chemical peeling, dermabrasion and laser resurfacing. Methylcellulose eyedrops and soft ultraviolet-protective contact lenses may be used to keep the cornea moist and protect against the harmful effects of keratitis sicca. Investigational therapies include the use of T4 endonuclease-V liposome lotion and oral nicotinamide to reduce the rate of actinic keratoses and non-melanoma skin cancers and gene therapy for radical cure of this condition. Conclusion: Although currently there is no cure for xeroderma pigmentosum, increased awareness and early diagnosis of the condition, followed by rigorous sun avoidance and protection and optimal management, can dramatically improve the quality of life and life expectancy.

[Clinical Characteristics and Gene Mutations in 186 Cases of Kindler Syndrome].

Objective To investigate the clinical characteristics and genetic mutations in Kindler syndrome(KS)and provide a theoretical basis for the diagnosis and treatment of KS. Methods The clinical data of one case of KS from Peking Union Medical College Hospital and 185 cases reported in literature were collected. The gene mutation types,patient clinical data,and tumor characteristics were statistically analyzed. Results A total of 186 cases were enrolled,including 110 males and 76 females,with the mean age of(28±16)years. The data of gene mutation and specific clinical manifestations were available in 151 and 94 patients,respectively. The main clinical manifestations of KS included poikiloderma,occurrence of blister in childhood,and photosensitivity,and the secondary clinical manifestations included oral inflammation,palmoplantar keratoderma,webbing/pseudoainhum,dysphagia,urethral stricture and so on.Oral inflammation(r=0.234,P=0.023),palmoplantar keratoderma(r=0.325,P=0.001),webbing/pseudoainhum(r=0.247,P=0.016),dysphagia(r=0.333,P=0.001),urethral stricture(r=0.280,P=0.006)were significantly correlated with age,showing significantly higher incidence in the patients over 32 years old.Urethral stricture(χ2=11.292,P=0.001)and anal stenosis(χ2=4.014,P=0.045)were significantly correlated with sex,with higher incidence in males.Eighty different mutations were found in 151 patients,and the most common gene mutation was c.676C>T.Forty-one tumors occurred in 27 patients,among which squamous cell carcinoma accounted for 92.7%. The gene mutation site had no significant correlation with squamous cell carcinoma or patient country. Conclusions The c.676C>T in FERMT1 gene is the most common mutation in KS.The patients are prone to squamous cell carcinoma and mainly attacked at the exposure sites(hand and mouth).

Rothmund-Thomson syndrome investigated by two nationwide surveys in Japan.

BACKGROUND: Rothmund-Thomson syndrome (RTS) is an autosomal recessive genetic disorder characterized by poikiloderma of the face, small stature, sparse scalp hair, juvenile cataract, radial aplasia, and predisposition to cancers. Due to the rarity of RTS, the situation of patients with RTS in Japan has not been elucidated. METHODS: In 2010 and 2020, following the results of a primary questionnaire survey, a secondary questionnaire survey on RTS was conducted nationwide to investigate the number of RTS cases and their associated skin lesions, bone lesions, other clinical features, and quality of life in Japan. RESULTS: In 2010 and 2020, 10 and eight patients with RTS were recruited, respectively. Skin lesions such as poikiloderma, erythema, pigmentation, and abnormal scalp hair were observed in almost all cases. Bone lesions were observed in four cases in the 2010 and 2020 surveys, respectively. Two cases had mutations in the RECQL4 gene in the 2020 survey. CONCLUSIONS: Two nationwide surveys have shown the actual situation of patients with RTS in Japan. Cutaneous and bone manifestations are important for the diagnosis of RTS. However, many patients have no RECQL4 mutations. The novel causative gene of RTS should be further elucidated.

Parapsoriasis-A Diagnosis with an Identity Crisis: A Narrative Review.

Parapsoriasis is an uncommon inflammatory skin disease characterized by chronic patches that may be resistant to therapy. It was primarily introduced and classified 120 years ago, and the original classification incorporated parapsoriasis and pityriasis lichenoides under the umbrella term parapsoriasis. After a major change in classification, parapsoriasis now exclusively refers to small plaque parapsoriasis (SPP) and large plaque parapsoriasis (LPP). However, debates still frequently occur regarding various nomenclatures and classifications used by different authors. Moreover, parapsoriasis may progress to overt cutaneous lymphoma, most commonly mycosis fungoides (MF), and it is very difficult to distinguish these two conditions despite modern histologic and molecular testing techniques.As parapsoriasis is a rare disease, there is a lack of studies and clinical guidelines to assist physicians in clinical practice. In our comprehensive review, we review several aspects of parapsoriasis, from the history of nomenclature and classification, clinical characteristics, immunohistopathology, and advanced molecular techniques for the diagnosis of this condition, to the most current treatments. We also propose a scheme for distinguishing parapsoriasis from early-stage MF in this review.

Mutations within the putative protease domain of the human FAM111B gene may predict disease severity and poor prognosis: A review of POIKTMP cases.

Mutations in the human FAM111B gene are associated with a rare, hereditary multi-systemic fibrosing disease, POIKTMP. To date, there are ten POIKTMP-associated FAM111B gene mutations reported in thirty-six patients from five families globally. To investigate the clinical significance of these mutations, we summarized individual cases by clinical features and position of the reported FAM111B gene mutations as those within and outside the putative protease domain (MWPPD and MOPPD respectively). MWPPD cases had more clinical manifestations than MOPPD (25 versus 18). Although the most common clinical features of poikiloderma, alopecia and hypohidrosis overall occurred in 94%, 86% and 75% of all cases with no significant differences between the MOPPD and MWPPD group, less common features included life-threatening (pulmonary fibrosis 47% vs. 13%; liver abnormalities specifically cirrhosis 26% vs. 7%) and physically disabling conditions (myopathy 53% vs. 20%; tendon contracture 55% vs. 7%) were more common in MWPPD cases. Similarly, the only 2 cases of POIKTMP with fatal pancreatic cancers were both only in the MWPPD group. This review thus suggests that mutations within the putative protease domain of the FAM111B protein are associated with a broader range of clinical features and may predict increased POIKTMP severity and a poorer prognosis.

Rothmund-Thomson syndrome: a case series from a tertiary pediatric hospital in Mexico.

BACKGROUND: Rothmund-Thomson syndrome, also known as congenital poikiloderma, is a rare autosomal recessive genodermatosis with onset in early childhood that affects at a multisystem level. CASE REPORTS: Case 1. A 4-year-old male patient, consanguineous parents, 26-year-old brother with a probable diagnosis of Rothmund-Thompson syndrome. He presented with adactyly of the right thumb, hypoplasia of the left thumb, delayed growth and psychomotor development. At 3 months, he presented rough, dry, sparse hair and erythematous lesions on the face, leaving hyperpigmented and hypopigmented spots with a reticulated pattern. We detected hypoacusis, skeletal alterations, narrow chin, short stature, severe malnutrition, and chronic and asymptomatic hypodontia. Genetic sequencing showed a mutation for the RECQL4 gene, for which a multidisciplinary follow-up was provided by the genetics, gastroenterology, nutrition, endocrinology, stomatology, audiology, orthopedics, rehabilitation, ophthalmology and oncology services. Case 2. A 2-year-old female patient presented facial erythema that spread to the arms and legs at 3 months; skin biopsy showed poikiloderma. She was evaluated by the endocrinology service and followed up for short stature and hypogonadism. A genetic study was not performed. CONCLUSIONS: Rothmund-Thomson syndrome is characterized by atrophy. Only a few cases are reported in the literature. We present two cases of Rothmund-Thomson syndrome, emphasizing its clinical and dermatological characteristics.

INTRODUCCIÓN: El síndrome de Rothmund-Thomson, también conocido como poiquilodermia congénita, es una rara genodermatosis autosómica recesiva de inicio en la infancia temprana y afectación multisistémica. CASOS CLÍNICOS: Se describen dos casos de pacientes con síndrome de Rothmund-Thomson. Caso 1. Paciente de sexo masculino de 4 años de edad, padres consanguíneos, hermano de 26 años con diagnóstico probable de síndrome de Rothmund-Thompson. Presentó adactilia del pulgar derecho, hipoplasia de pulgar izquierdo, retraso en el crecimiento y retraso del desarrollo psicomotor. A los 3 meses de edad mostraba pelo áspero, seco y escaso, y lesiones eritematosas en la cara, las cuales dejaron manchas hiperpigmentadas e hipopigmentadas con patrón reticulado. Se detectaron hipoacusia, alteraciones esqueléticas, mentón estrecho, talla baja, desnutrición grave e hipodontia crónica y asintomática. La secuenciación genética resultó con mutación para el gen RECQL4, por lo que se dio seguimiento multidisciplinario por los servicios de genética, gastroenterología, nutrición, endocrinología, estomatología, audiología, ortopedia, rehabilitación, oftalmología y oncología. Caso 2. Paciente de sexo femenino de 2 años de edad que a los 3 meses de vida inició con eritema facial que se diseminó a los brazos y la piernas; la biopsia de piel reportó poiquilodermia. Se encuentra en seguimiento por el servicio de endocrinología por talla baja e hipogonadismo. No se realizó estudio genético. CONCLUSIONES: El síndrome de Rothmund-Thomson se caracteriza por atrofia. Existen pocos casos reportados en la literatura. Se presentan dos casos de síndrome de Rothmund-Thomson, enfatizando sus características clínicas y dermatológicas.

A new treatment option for poikiloderma of Civatte: 577 nm pro-yellow laser.

BACKGROUND: Although many laser systems have been used in the treatment for Poikiloderma of Civatte (POC), there is no standard treatment guideline. OBJECTIVES: We aimed to present our data on the efficacy and safety of single-session pro-yellow laser treatment for POC. METHODS: The study included 14 patients treated with pro-yellow laser (QuadroStarPRO YELLOW® Asclepion Laser Technologies, Germany) between 2017 and 2019. Treatment had been applied in two passes during the same session; a general pass with 22 j/cm2 over the whole lesion, then, one more pass only on the telangiectatic lesions with 18 j/cm2 fluence. They were evaluated based on their pictures taken before and 4 weeks after the treatment and scored by a 4-item scoring in terms of the improvement (0:no change, 1:1%-25% mild, 2:26%-50% moderate, 3:51%-75% well, and 4:76%-100% excellent improvement). RESULTS: The mean age of the patients (1 female, 13 males) was 59.64 ± 8.16 years. Five patients had Fitzpatrick-2 and 9 patients had Fitzpatrick-3 skin types. Six patients had mild, 8 patients had moderate improvement, one of them has been illustrated in Figure 1. Sixty-minute mild erythema was the only adverse effect observed. CONCLUSIONS: We think that pro-yellow laser is a good treatment option for POC treatment. Repeated sessions are required for the complete healing of the lesions, while one single session has proved to be deficient. We observed that it was a quite safe treatment option, especially for the neck region, which was inclined to scarring and atrophy development.