Two Japanese patients with Noonan syndrome-like disorder with loose anagen hair 2.

Noonan syndrome-like disorder with loose anagen hair (NSLH) is a rare disease characterized by typical features of Noonan syndrome with additional findings of relative or absolute macrocephaly, loose anagen hair, and a higher incidence of intellectual disability. NSLH1 is caused by a heterozygous mutation in the SHOC2 gene on chromosome 10q25, and NLSH2 is caused by a heterozygous mutation in the Protein phosphatase one catalytic subunit beta (PPP1CB) gene on chromosome 2p23. Protein phosphatase1 (PP1), encoded by PPP1CB, forms a complex with SHOC2 and dephosphorylates RAFs, which results in activation of the signaling cascade and contribution to Noonan syndrome pathogenesis. Here, we report two genetically confirmed Japanese patients with NSLH2 having the same de novo mutation in PPP1CB presenting prominent-hyperteloric-appearing eyes and a tall forehead similar to individuals carrying a mutation in PPP1CB, c.146C > G; p.Pro49Arg, which is different from typical facial features of Noonan syndrome. They also showed short stature, absolute macrocephaly, and loose anagen hair like NSLH1: however, growth hormone deficiency often seen in NSLH1 caused by SHOC2 mutation was absent. Although a number of Noonan syndrome and NSLH1 patients have shown blunted or no response to GH therapy, linear growth was promoted by recombinant human growth hormone (rhGH) in one of our patients. Since another NSLH2 patient with good response to rhGH treatment was reported, rhGH therapy may be effective in patients with NSLH2.

Noonan syndrome with loose anagen hair with variants in the PPP1CB gene: First familial case reported.

Rasopathies are a group of phenotypically overlapping conditions that include Noonan, Noonan with multiple lentigines, Noonan with loose anagen hair, Costello, Cardio-facio-cutaneous, and Neurofibromatosis-Noonan syndromes. Noonan syndrome with loose anagen hair (NS-LAH) is clinically characterized by prominent forehead, macrocephaly, growth hormone deficiency, sparse, loose and slow-growing anagen hair, hyperpigmented skin with eczema or ichthyosis, mild psychomotor delays, hypernasal voices, and attention deficit hyperactivity disorder. Variants in SHOC2 are responsible for the majority of the cases. Gripp et al. identified four unrelated individuals with similar phenotype to NS-LAH with pathogenic variants in PPP1CB. In this study, we present one family and one patient with NS-LAH and variants in PPP1CB. The first patient belongs to a family with a likely pathogenic variant, c.545T>A (p.Met182Lys), the first family published so far with a variant in this gene. The second patient harbors a de novo pathogenic variant, c.146C>G (p.Pro49Arg). This study presents two additional patients with this rare syndrome in order to increase the clinical characterization of the syndrome and provide more evidence of the pathogenicity of the c.545T>A (p.Met182Lys) variant in PPP1CB, a gene recently associated with NS-LAH.

A case report of Noonan syndrome-like disorder with loose anagen hair 2 treated with recombinant human growth hormone.

Protein phosphatase 1 catalytic subunit beta (PPP1CB) is a disease-causing gene of Noonan-like syndrome, which acts via the RAS/MAPK pathway. To date, only 17 patients diagnosed with PPP1CB-related Noonan-like syndrome have been reported around the world, with few reports in Asia. Twelve reported patients are of short stature and only one patient was treated with growth hormone (GH); however, follow-up data is lacking. To the best of our knowledge, this is the first reported patient with complete recombinant human growth hormone (rhGH) treatment follow-up data; the patient has a de novo c.146C>G (p.Pro49Arg) mutation in the PPP1CB gene. The hair pattern of the patient (coarse, curly, slow growing, and fragile) combined with Noonan dysmorphic features, developmental delay, and congenital heart disease, are highly consistent with the typical features observed in Noonan syndrome-like disorder with loose anagen hair 2 (NSLH2). rhGH treatment, administered for 3 years and 8 months, promoted the patient's linear growth. Our findings expand the data regarding the treatment of short stature in patients with NSLH2 caused by PPP1CB mutation. Clinical manifestation, growth and development process, and rhGH therapy effect data will aid in future revision of the relevant diagnosis and treatment guidelines.

N(1)-methylspermidine, a stable spermidine analog, prolongs anagen and regulates epithelial stem cell functions in human hair follicles.

Spermidine (Spd), the prototypic polyamine, has been shown to be essential for hair follicle (HF) growth. However, Spd can be readily converted into other polyamines, and is physiologically unstable. Therefore, to assess its individual functions on HFs, we used the metabolically stable Spd analog N(1)-methylspermidine (N(1)-MeSpd). N(1)-MeSpd was confirmed to be a metabolically stable compound, with a half life of 90 h. 0.5 µM N(1)-MeSpd strongly prolonged anagen and decreased cell apoptosis in HFs in culture after 6 days, accompanied by specific stimulation of the expression of the epithelial stem cell-associated keratin, K15. N(1)-MeSpd also reduced lactate dehydrogenase activity in the culture supernatant, a parameter of cell death and cell lysis. N(1)-MeSpd diminished intracellular reactive oxygen species production in cultured keratinocytes, and reduced tumor necrosis factor-α, interleukin (IL)-1ß and IL-6 gene and protein expression after lipopolysaccharide stimulation. This suggests that some effects of N(1)-MeSpd may be mediated by anti-oxidative and anti-inflammatory effects. These additional properties of N(1)-MeSpd could be clinically important for the treatment of inflammatory alopecias and inflammatory scalp diseases.

Improved growth velocity of a patient with Noonan-like syndrome with loose anagen hair (NS/LAH) without growth hormone deficiency by low-dose growth hormone therapy.

Noonan-like syndrome with loose anagen hair (NS/LAH; OMIM 607721) is caused by a heterozygous c.4A>G mutation in SHOC2. Most cases exhibit both growth hormone deficiency (GHD) and growth hormone insensitivity (GHI) and thus require a high dose of growth hormone (GH) therapy (e.g., 35-40 µg/kg/day). We report on a genetically diagnosed NS/LAH patient manifesting severe short stature (-3.85 SDs) with low serum level of IGF1, 30 ng/ml. The peak levels of GH stimulation tests were within the normal range, and GHI was not observed in the IGF1 generation test. However, with low-dose GH therapy (25 µg/kg/day) for two years, IGF1 level and height were remarkably improved (IGF1: 117 ng/ml, height SDs: -2.20 SDs). Further, catch-up of motor development and improvement of the proportion of extending limbs to trunk were observed (the Developmental Quotient score increased from 68 to 98 points, and the relative sitting height ratio decreased from 0.62 to 0.57). Our results suggest that endocrinological causes for short stature are variable in NS/LAH and that GH therapy should be considered as a possible treatment for delayed development in NS/LAH.

Moyamoya disease in two patients with Noonan-like syndrome with loose anagen hair.

Moyamoya disease is a unique chronic cerebrovascular condition caused by progressive stenosis of the arteries around the circle of Willis with prominent arterial collateral circulation. Noonan-like syndrome with loose anagen hair (NSLH) is characterized by short stature, characteristic facial phenotype, darkly pigmented and hairless skin, mild psychomotor delay with attention deficit disorder, and easily pluckable, sparse, thin, slow growing hair. Mutations in SHOC2 have been reported to underlie NSLH. In this paper, we describe two individuals with NSLH who also have moyamoya disease and in whom heterozygous germline mutation in SHOC2 was found.

A case of loose anagen syndrome in an African American girl.

We present the case of 7-year-old African American girl with loose anagen syndrome. Although this is a common cause of hair loss in Caucasian children, and there have been reports of cases occurring in dark-skinned children of North African and Middle Eastern descent, to our knowledge there have been no cases reported in black children of sub-Saharan African ancestry. We present this case to broaden the differential diagnosis of hair loss in African Americans.

Phenotypic variability associated with the invariant SHOC2 c.4A>G (p.Ser2Gly) missense mutation.

Noonan-like syndrome with loose anagen hair (NS/LAH; OMIM 607721) is a developmental disorder clinically related to Noonan syndrome (NS) and characterized by facial dysmorphisms, postnatal growth retardation, cardiac anomalies (in particular dysplasia of the mitral valve and septal defects), variable neurocognitive impairment, and florid ectodermal features. A distinctive trait of NS/LAH is its association with easily pluckable, slow growing, sparse, and thin hair. This rare condition is due to the invariant c.4A > G missense (p.Ser2Gly) change in SHOC2, which encodes a regulatory protein that participate in RAS signaling. Here we report two patients with molecularly confirmed NS/LAH, with extremely different phenotypic expression, in particular concerning the severity of the cardiac phenotype and neurocognitive profile. While the first available clinical records outlined a relatively homogeneous phenotype in NS/LAH, the present data emphasize that the phenotype spectrum associated with this invariant mutation is wider than previously recognized.

Loose anagen hair syndrome in black-haired Indian children.

Loose anagen hair syndrome (LAHS) is an uncommonly reported autosomal dominant hair disorder with incomplete penetrance that primarily affects children but is occasionally seen in adults. LAHS is characterized by the ability to easily and painlessly extract unsheathed anagen hairs from the scalp with gentle traction. The hair is sparse and does not grow long. Usually the hairs are not fragile and do not have areas of breakage. Initially it was considered a rare, sporadic condition found predominantly in young white girls with blonde hair. Because autosomal dominant inheritance has been reported, it was suspected that the condition might be equally common in boys but was probably underdiagnosed.

Short anagen syndrome.

Short anagen syndrome (SAS) is a recently described disease, but is rarely reported in the literature probably because of its under-recognized status. It is characterized by the inability to grow long hair because of an idiopathic short anagen phase. The condition is not associated with hair shaft fragility or hair unruliness. The patients complain of abnormally short scalp hair and report that they never had a haircut. The condition is benign and most of the reported cases had no associated systemic diseases or skin disorders. Hair length tends to improve spontaneously after puberty. The main differential diagnoses include loose anagen hair syndrome (LAS).

Abnormal inner root sheath of the hair follicle in the loose anagen hair syndrome: an ultrastructural study.

BACKGROUND: Loose anagen hair syndrome (LAHS) is a disorder in which the hair pulls out easily and painlessly from the scalp. It first manifests in early childhood when the main concern of parents is that the sparse hair does not grow. The hair density and length improve with age, but the looseness persists into adulthood. OBJECTIVE: Light and electron microscopic studies of hair follicles were performed to better define the microscopic changes seen in LAHS. METHODS: Biopsy specimens were obtained from 4 patients, 3 children and 1 adult. The hair follicles were studied by light and electron microscopy. RESULTS: The most conspicuous structural changes were found in the inner root sheath complex of the anagen follicle. With light microscopy, the keratinized Henle cell layer showed a tortuous and irregular swelling. Irregular keratinization of the cuticle cells of the inner root sheath and a swollen appearance of Huxley cells were also found. With electron microscopy, the major pathological changes consisted of intercellular edema in the prekeratinized Huxley cell zone and dyskeratosis of Henle cells and cuticle cells of the inner root sheath. LIMITATIONS: The studies were done on a small number of patients. CONCLUSIONS: Structural abnormalities of the inner root sheath appear to disturb its normal supportive and anchoring function and result in a loose attachment of the hair shaft to the anagen follicle.

Poorly growing hair in a child.

A healthy 5-year-old Caucasian girl presented to the pediatric dermatology clinic for poor hair growth. The patient's father described slow hair growth and finely textured hair since birth. The patient had her first haircut 1 month before presentation. The family denied bald areas on the scalp, significant hair shedding, and sores on the scalp. The child did not scratch at her scalp or pull her hair. She are a normal diet and had normal growth and development otherwise. She was not taking any medications or over-the-counter supplements. There was no family history of hair disorders. On physical examination, the patient had short, fine, reddish blond hair that was of different lengths (Figure 1). There were no papules, pustules, scale, or crust on her scalp. Lymphadenopathy was absent. She had normal eyelashes and eyebrows. There were no lesions on her oral mucosa. No tooth or nail abnormalities were present. The rest of the physical examination was normal. The hair pull test resulted in 4 easily pulled hairs (3 anagen and 1 telogen). A hair mount was performed (Figure 2). The hair mount analysis revealed anagen hairs with distorted bulbs and ruffled cuticles extending a short distance distally from the bulb, consistent with loose anagen hair (Figure 2). All of the anagen hairs on the pull test demonstrated the above findings. Based on the patient's clinical presentation and the findings seen on light microscopy of the hair mount preparation, the patient was diagnosed with loose anagen syndrome.

Short anagen syndrome in an African American woman.

Short anagen syndrome is an uncommon condition characterized by the inability to grow long hair and an increase in the number of hairs in telogen. The incidence of short anagen syndrome is poorly documented in the medical literature. In all reports, patients are Caucasian and usually have fine blond hair. We report a case of a 38-year-old African American woman with short anagen syndrome.