BACKGROUND: Autosomal-dominant brachydactyly type E is a congenital abnormality characterized by small hands and feet, which is a consequence of shortened metacarpals and metatarsals. We recently encountered a young gentleman exhibiting shortening of 4th and 5th fingers and toes. Initially, we suspected him having pseudopseudohypoparathyroidism (PPHP) because of normal biochemical parameters, including electrolyte, Ca, P, and parathyroid hormone (PTH) levels; however, his mother and maternal grandmother had the same conditions in their hands and feet. Furthermore, his mother showed normal biochemical parameters. To the best of our knowledge, PPHP is inherited via a mutated paternal allele, owing to the paternal imprinting of GNAS (guanine nucleotide binding protein, alpha stimulating) in the renal proximal tubule. Therefore, we decided to further analyze the genetic background in this family. METHODS: Whole exome sequencing was performed using genomic DNA from the affected mother, son, and the unaffected father as a negative control. RESULTS: We selected the intersection between 45,490 variants from the mother and 45,646 variants from the son and excluded 27,512 overlapping variants identified from the father. By excluding homogenous and compound heterozygous variants and removing all previously reported variants, 147 variants were identified to be shared by the mother and son. Variants that had least proximities among species were excluded and finally 23 variants remained. CONCLUSION: Among them, we identified a defect in parathyroid hormone like hormone (PTHLH), encoding the PTH-related protein, to be disease-causative. Herein, we report a family affected with brachydactyly type E2 caused by a novel PTHLH mutation, which was confused with PPHP with unclassical genetic penetrance.
Alleles ; Brachydactyly* ; Carrier Proteins ; Congenital Abnormalities ; DNA ; Exome ; Fathers ; Fingers ; Foot ; Genetic Background ; Grandparents ; Hand ; Humans ; Metacarpal Bones ; Metatarsal Bones ; Mothers ; Parathyroid Hormone ; Parathyroid Hormone-Related Protein ; Penetrance ; Pseudopseudohypoparathyroidism* ; Toes

Polyglandular autoimmune syndrome is defined as multiple endocrine gland insufficiencies accompanied by autoimmune diseases of the endocrine and nonendocrine system. After Schmidt introduced a case of nontuberculosis adrenal gland dysfunction with thyroiditis in 1926, Neufeld defined polyglandular autoimmune syndrome by I, II, and III subtypes in 1980 by their presentation of occurrence age, heredity methods, relationship with human leukocyte antigen, and accompanying diseases. We report a case of a 32-year-old female with polyglandular autoimmune syndrome III accompanied by type 1 diabetes mellitus that was treated with insulin (36 units per day) for 11 years. She had insulin deficiency and Hashimoto thyroiditis as an autoimmune disorder. In addition, she had several features similar to Albright's hereditary osteodystrophy including short stature, truncal obesity, round face, short neck, low intelligence (full IQ 84), and decreased memory. Although Albright's hereditary osteodystrophy is morphological evidence of pseudohypoparathyroidism or pseudopseudohypoparathyroidism, she had primary hypoparathyroidism on laboratory results. Here, we report a case of polyglandular autoimmune syndrome III with type 1 diabetes mellitus, autoimmune thyroiditis, and primary hypoparathyroidism, accompanied by clinical features similar to Albright's hereditary osteodystrophy.
Adrenal Glands ; Adult ; Autoimmune Diseases ; Diabetes Mellitus, Type 1 ; Endocrine Glands ; Female ; Fibrous Dysplasia, Polyostotic ; Hashimoto Disease ; Heredity ; Humans ; Hypoparathyroidism ; Insulin ; Intelligence ; Leukocytes ; Memory ; Neck ; Obesity ; Pseudohypoparathyroidism ; Pseudopseudohypoparathyroidism ; Thyroid Gland ; Thyroiditis ; Thyroiditis, Autoimmune

Primary osteoma cutis is characterized by the formation of normal bone tissue in the dermis or subcutis without any underlying tissue abnormality or pre-existing calcification. This illness is associated with Albright hereditary osteodystrophy (AHO), which is characterized by such physical features as a short stature, round face, obesity, brachydactyly and osteoma cutis. Pseudohypoparathyroidism (PHP) is an inherited metabolic disorder that's characterized by resistance to parathyroid hormone, and PHP is present in most AHO patients. An AHO phenotype without hormonal resistance is called pseudopseudohypoparathyroidism (PPHP). Osteoma cutis is less common in patients with PPHP than in patients with PHP. We present here a case of osteoma cutis as the cardinal manifestation of AHO associated with PPHP. Osteoma cutis is an important sign of AHO and its significance should not be overlooked, even if the patient has normal values on the serum biochemical tests.
Alkenes ; Bone and Bones ; Bone Diseases, Metabolic ; Brachydactyly ; Dermis ; Fibrous Dysplasia, Polyostotic ; Humans ; Obesity ; Ossification, Heterotopic ; Osteoma ; Parathyroid Hormone ; Phenotype ; Pseudohypoparathyroidism ; Pseudopseudohypoparathyroidism ; Reference Values ; Skin Diseases, Genetic

Primary osteoma cutis is characterized by the formation of normal bone tissue in the dermis or subcutis without any underlying tissue abnormality or pre-existing calcification. This illness is associated with Albright hereditary osteodystrophy (AHO), which is characterized by such physical features as a short stature, round face, obesity, brachydactyly and osteoma cutis. Pseudohypoparathyroidism (PHP) is an inherited metabolic disorder that's characterized by resistance to parathyroid hormone, and PHP is present in most AHO patients. An AHO phenotype without hormonal resistance is called pseudopseudohypoparathyroidism (PPHP). Osteoma cutis is less common in patients with PPHP than in patients with PHP. We present here a case of osteoma cutis as the cardinal manifestation of AHO associated with PPHP. Osteoma cutis is an important sign of AHO and its significance should not be overlooked, even if the patient has normal values on the serum biochemical tests.
Alkenes ; Bone and Bones ; Bone Diseases, Metabolic ; Brachydactyly ; Dermis ; Fibrous Dysplasia, Polyostotic ; Humans ; Obesity ; Ossification, Heterotopic ; Osteoma ; Parathyroid Hormone ; Phenotype ; Pseudohypoparathyroidism ; Pseudopseudohypoparathyroidism ; Reference Values ; Skin Diseases, Genetic

Albright's hereditary osteodystrophy (AHO) has a broad spectrum of physical findings, including short stature, flattened nasal bridge, round facies, obesity, skeletal anomalies of the hands with brachydactyly, osteoma cutis, mental retardation, dental defects, cataracts, and calcification in the basal ganglia. It also includes endocrinologic abnormalities such as pseudohypoparathyroidism and pseudopseudohypoparathyroidism. Primary osteoma cutis, which can precede other physical findings of AHO, might be a diagnostic clue for AHO. Therefore, close follow-up and regular laboratory tests should be done to detect the early development of AHO in young children with primary osteoma cutis. Early diagnosis and treatment of AHO can prevent irreversible mental retardation and developmental delay.
Basal Ganglia ; Bone Diseases, Metabolic ; Brachydactyly ; Cataract ; Child ; Early Diagnosis ; Facies ; Fibrous Dysplasia, Polyostotic ; Hand ; Humans ; Intellectual Disability ; Obesity ; Ossification, Heterotopic ; Osteoma ; Pseudohypoparathyroidism ; Pseudopseudohypoparathyroidism ; Skin Diseases, Genetic

A 36 year-old man and his 6 month-old daughter presented with multiple, slightly depressed, skin-colored, hard nodules and plaques on the abdomen, back, and both extremities. They also showed abnormal physical appearance, including short stature and neck, round face, and short digits, which suggested Albright's hereditary osteodystrophy (AHO). Histopathologically, various sized bony spicules were present in the dermis. The laboratory results showed normal serum calcium, phosphorus and parathyroid hormone levels. On the basis of clinical, laboratory and histologic findings, we diagnosed these cases as Albright's hereditary osteodystrophy with cutaneous ossification occurring in pseudopseudohypoparathyroidism.
Abdomen ; Calcium ; Dermis ; Extremities ; Fibrous Dysplasia, Polyostotic ; Neck ; Nuclear Family ; Parathyroid Hormone ; Phosphorus ; Pseudopseudohypoparathyroidism

A 36 year-old man and his 6 month-old daughter presented with multiple, slightly depressed, skin-colored, hard nodules and plaques on the abdomen, back, and both extremities. They also showed abnormal physical appearance, including short stature and neck, round face, and short digits, which suggested Albright's hereditary osteodystrophy (AHO). Histopathologically, various sized bony spicules were present in the dermis. The laboratory results showed normal serum calcium, phosphorus and parathyroid hormone levels. On the basis of clinical, laboratory and histologic findings, we diagnosed these cases as Albright's hereditary osteodystrophy with cutaneous ossification occurring in pseudopseudohypoparathyroidism.
Abdomen ; Calcium ; Dermis ; Extremities ; Fibrous Dysplasia, Polyostotic ; Neck ; Nuclear Family ; Parathyroid Hormone ; Phosphorus ; Pseudopseudohypoparathyroidism

Albright's hereditary osteodystrophy is an inherited syndrome that encompasses endocrinologic anomaly of pseudohypoparathyroidim or less commonly, pseudo-pseudohypoparathyroidism and various physical stigmata such as mental retardation, short stature, skeletal anomaly of the hands, abnormal dentition, round facies, and osteoma cutis. Primary osteoma cutis in this syndrome presents at birth or in early infancy, preceding most of the other manifestations. This case is a typical presentation with osteoma cutis as the sole initial manifestation. Rather unfamiliar to dermatologists, Albright's hereditary osteodystrophy still deserves to be included in the differentials when an isolated case of osteoma cutis presents in a young child.
Child ; Christianity ; Dentition ; Facies ; Hand ; Humans ; Intellectual Disability ; Osteoma* ; Parturition ; Pseudopseudohypoparathyroidism

Pseudohypoparathyroidism (PHP) is a rare endocrine syndrome, which is characterized by Albright's hereditary osteodystrophy (AHO). Pseudopseudohypoparathyroidism (PPHP) presents with AHO features, but does not show clinical symptoms or the same laboratory finding as hypoparathyroidism. A 54 aged woman visited our department with lower abdominal pain. She had a history of a total hysterectomy due to persistent uterine bleeding 30 years previously. She showed abnormal physical findings, including a round face, short stature and brachydactyly. Her hormonal data were within normal limits, as follows: PTH 40.72 pg/mL, calcium 8.6 mg/dL, phosphorus 4.0 mg/dL and 24 hour urine cAMP 3.2 nmol/mg. On a pituitary challenge test, the basal levels and response rates of FSH and LH were low, and a sella CT scan showed partially empty sella. Herein is reported a case of PPHP, with partial empty sella, with a review of the literature
Abdominal Pain ; Brachydactyly ; Calcium ; Female ; Humans ; Hypoparathyroidism ; Hysterectomy ; Phosphorus ; Pseudohypoparathyroidism ; Pseudopseudohypoparathyroidism* ; Tomography, X-Ray Computed ; Uterine Hemorrhage

Pseudohypoparathyroidism (PHP) is a rare endocrine syndrome, which is characterized by Albright's hereditary osteodystrophy (AHO). Pseudopseudohypoparathyroidism (PPHP) presents with AHO features, but does not show clinical symptoms or the same laboratory finding as hypoparathyroidism. A 54 aged woman visited our department with lower abdominal pain. She had a history of a total hysterectomy due to persistent uterine bleeding 30 years previously. She showed abnormal physical findings, including a round face, short stature and brachydactyly. Her hormonal data were within normal limits, as follows: PTH 40.72 pg/mL, calcium 8.6 mg/dL, phosphorus 4.0 mg/dL and 24 hour urine cAMP 3.2 nmol/mg. On a pituitary challenge test, the basal levels and response rates of FSH and LH were low, and a sella CT scan showed partially empty sella. Herein is reported a case of PPHP, with partial empty sella, with a review of the literature
Abdominal Pain ; Brachydactyly ; Calcium ; Female ; Humans ; Hypoparathyroidism ; Hysterectomy ; Phosphorus ; Pseudohypoparathyroidism ; Pseudopseudohypoparathyroidism* ; Tomography, X-Ray Computed ; Uterine Hemorrhage