History
Growth delay is the most impressive clinical feature of Bloom syndrome (congenital telangiectatic erythema) and is usually the first manifestation that causes the parents to seek medical attention. Other associated physical features and immunodeficiency are not present or recognizable at birth. The growth deficiency has a prenatal onset, apparent from term birth measurements, and persists throughout life. More than half the children are significantly underdeveloped in physical stature until age 8 years.
Patients with Bloom syndrome demonstrate recurrent respiratory and gastrointestinal tract infections.
Physical Examination
Physical examination findings in Bloom syndrome (congenital telangiectatic erythema) vary and involve stunted growth, cutaneous manifestations, ocular manifestations, musculoskeletal manifestations, fertility concerns, immunologic manifestations, and a predisposition to malignancies, among others.
Stunted growth
Prenatal and postnatal growth deficiency is noted in Bloom syndrome patients. The length and weight are both affected, but with normal body proportion (primordial stunted growth). The average birth weight reported for children with Bloom syndrome was 1.868 g in females and 1.890 g in males. [22] The child typically has reduced subcutaneous fat, yielding a wasted appearance. Small stature results from intrauterine growth restriction and the constant postnatal growth restriction. [23]
The mean final adult stature reported in males was 148.5 cm and 141.5 cm in females, with a mean weight of 41.3 kg in males and 36.6 kg in females. [22] Despite this stunted growth, normal growth hormone production and secretion was noticed in these patients, as well as normal serum concentrations of insulinlike growth factor 1 and insulinlike growth factor binding protein 3.
Feeding problems
Feeding problems are typically significant in infants and children. There is lack of interest in eating. Some patients have gastroesophageal reflux, vomiting, and diarrhea. The low body mass index in these children was noted to improve after age 8 years, and some adults developed central obesity. [24]
Cutaneous manifestations
Skin findings in Bloom syndrome include telangiectatic erythema, which is usually not congenital, appearing on average at age 8 years. It appears as macules or plaques in a butterfly distribution on the face and other photodistributed areas (eg, ears, eyelids, forearms, dorsa of the hands). Blistering, hemorrhage and crusts may occur.
Patients with a dark skin phenotype demonstrate fewer cutaneous manifestations. Absence of photosensitivity, facial erythema, and telangiectasia was reported in Japanese and Latin American patients. [25]
The characteristic rash develops later in life, mainly on the face following a butterfly distribution on the cheeks and nose, mostly in the form of telangiectasia and erythema. It is exacerbated by sun exposure and may develop on other sun-exposed skin such as the dorsum of hands, forearms, and ears. [26]
Other cutaneous manifestations reported include cheilitis, fissuring, blistering, poikiloderma, eyebrow or eyelash hair loss, and alopecia areata. [27]
Extensive vesicular and bullous eruptions have been reported with sun exposure, and an absence of the characteristic photosensitivity has also been reported. [28, 29]
Café au lait macules with adjacent hypopigmented areas appear as twin spotting. They are fewer and smaller than in non–Bloom syndrome patients. [30]
There is increased risk for skin cancers. Basal cell carcinoma is the most common, followed by squamous cell carcinoma. Melanomas have not been reported in Bloom syndrome patients. [31] Most cancers had occurred in sun-exposed skin, but skin of hip and base of the penis have been reported. [32] Multiplicity of skin cancer in individual patients is uncommon. However, multiple basal cell carcinomas on the face and neck in a Bloom syndrome patient have been reported. [33]
Facial features
Bloom syndrome patients show variable facial features, commonly a long and narrow face, retrognathia or micrognathia, and an underdeveloped malar area. The head circumference of most patients with Bloom syndrome is below the third percentile. The nose and/or ears of Bloom syndrome patients are often prominent, owing to the decreased amount of subcutaneous fat. [22]
Ocular manifestations
Scleral telangiectasias, bulbar conjunctival telangiectasia, conjunctivitis, sectoral iris pigment alteration, lens opacities, leukemic retinopathy, retinoblastoma, lateral strabismus, ectropion, and bilateral optic nerve hypoplasia are reported. [34, 35]
Musculoskeletal abnormalities
Affected individuals have long limbs, disproportionally large hands and feet, and progressive contracture of hands and feet. Upper extremities are long in proportion to body length.
Quick, birdlike movements are characteristic.
Clinodactyly and syndactyly may be seen. [36]
Fertility
Male patients are infertile (primary hypogonadism), and female patients are subfertile (premature menopause).
Immunologic abnormalities
Patients with Bloom syndrome are predisposed to respiratory and gastrointestinal infections as a result of a deficiency of immunoglobulin A. [17] Bacterial infections are more frequent than viral infections. Chronic lung disease is the second leading cause of death in Bloom syndrome patients. [37]
It should be noted that most Bloom syndrome patients do not have meningitis, bacterial sepsis, pneumonia, recurrent abscesses, or opportunistic infections, as are seen in primary immunodeficiency patients. [38]
Predisposition to malignancy
There is marked predisposition to early development of cancer. About 25% of patients develop malignancy, at a mean age of 20.7 years. Neoplasms of all types and sites may develop. The most common cancers reported in Bloom syndrome include lymphomas, leukemia, oral/esophageal squamous cell carcinoma, and adenocarcinoma of the sigmoid colon. [39]
More than one cancer occurring in a patient has been reported. [40] BLM mutation was found to increase the susceptibility to breast cancer, and a higher probability of colorectal carcinoma was found in heterozygous carriers of the BLM mutation. [41, 42] Bloom syndrome registry data suggest that 46% of registered patients develop cancers, with epithelial tumors being most frequent (52.5%), followed by lymphoid neoplasms (24%). [20] It was reported that 12% of Bloom syndrome patients develop colorectal cancer, mainly in their second decade of life. [40]
Other general associations
Patients have a high-pitched voice. Congenital heart disease and annular pancreas have been reported. Type 2 diabetes mellitus develops in about 15% of patients, and the risk increases with age. [37] Severe pulmonary involvement with parenchymal destruction, respiratory failure, emphysema, and bronchiectasia has been reported in Bloom syndrome. It has been suggested that recurrent lower respiratory tract infections since childhood could play a role in these changes. [43, 44] Other uncommon features include eyebrow hair loss, alopecia areata, reticular pigmentation on the forehead and trunk, flat nose, wide fingernails, and short sharpened distal phalanges. [45]
Complications
Men with Bloom syndrome (congenital telangiectatic erythema) are sterile; women have reduced fertility and a shortened reproductive span.
Recurrent respiratory and gastrointestinal tract infections and the development of chronic lung disease are additional complications, as is the early development of different types of cancers at any site. Type 2 diabetes is found in 15.8% of patients. [20]
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Crystal structure of the Bloom syndrome helicase BLM in complex with DNA (PDB ID: 4CGZ). Courtesy of Arthur Zalevsky (own work), via Wikimedia Commons.
