| Phenotype and clinics | Growth:
Short stature with prenatal onset (birth length and birth weight 1.5 - 2 SD below mean with relatively macrocephaly - occipitofrontal head circumference 0.5 below SD; adult male height 136-161 cm; adult female height 126-151 cm) (Karlberg et al.2006)
Head:
Craniofacial features: triangular face, low nasal bridge, high and broad forehead, and scaphocephaly with occipitofrontal bossing
Eye findings: Mild hypertelorism, telecanthus, yellowish dots in fundi, decreased retinal pigmentation with dispersion, hypoplasia of choroid, astigmatism, strabismus (Karlberg et al.2004)
Mouth: relatively small tongue, dental crowding, hypodontia of second bicuspid (Myllarniemi et al. 1978)
Cardiovascular System:
Constrictive pericarditis, globular shaped heart on x-ray, congestive heart failure, myocardial fibrosis, elevated venous pressure, prominent veins in the neck, congestion in the lungs, abnormal fluid accumulation in the abdomen (ascites), swelling of the arms and/or legs (peripheral edema) (Perheentupa et al.1973; Cumming et al.1976)
Abdomen: hepatomegaly, sporadic description of urinary tract malformations
Muscle: muscular hypotonia
Central Nervous System: no intellectual disability, dysarthria
Voice: high-pitched voice
Skin: cutaneous nevi flammei
Endocrinology: delayed puberty with irregular menstrual periods, premature ovarian failure, incomplete breast development, infertility, insuline resistance type2 diabetes,possible hypoplasia of different endocrine glands(Haraldsson 1993; Kalberg et al.2004; Karlberg et al.2007).
Radiological findings:
Cerebral: J-shaped sella turcica, absent or small frontal sinus, absent or small sphenoidal sinus
Skeletal: slender long bones with thick cortex and narrow medullary channel, fibrous dysplasia especially in the middle third of tibia. |
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| | Three major signs with one minor sign or two major signs with three minor signs are required for the clinical diagnosis. SDS = standard deviation scores. Adapted by Karlberg et al. 2004. |
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| Differential diagnosis | Mulibrey nanism shares some clinical aspects mainly with two other syndromes (Silver Russel Syndrome and 3-M syndrome spectrum (OMIM 273750)) characterized by growth failure and dysmorphic features (Akawi et al.2011). |
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| | Comparison between Mulibrey Nanism, Silver-Russell and 3-M Syndromes phenotype. |
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| Neoplastic risk | Benign tumors especially cystic and benign adenomatous lesions have been identified in different organs (renal cortical cysts, pancreatic cysts, thyroid lesions); the 22% of patients develop fibrous dysplasia of long bones; 6% of reported patients were diagnosed for a Wilms tumor. Female patients with premature ovarian failure are at high risk for ovarian fibrothecomas or other stromal ovarian cells tumors (Hamalainen et al., 2006; Karlberg et al. 2009). |
| Treatment | Patients with constrictive pericarditis may be treated with surgery with good results, while treatment with diuretics and digoxin may be prescribed for those affected by progressive heart failure. Hormone replacement therapy may be evaluated in children with growth hormone deficiency, delayed puberty or very irregular menstrual periods, hypothyroidism, hypoadrenocorticism and abnormal gonadal function. All females should be monitored closely for ovarian tumors, especially in presence of premature ovarian failure (Hamalainen et al., 2006; Karlberg et al. 2006; Karlberg et al. 2009). |
| Evolution | Growth failure usually progresses during early infancy; after 10 years of age blood fasting glucose levels tend to increase; the diagnosis of Wilms'tumour is usually close to 1 year of age, while after puberty all female should undergo to a gynaecological follow-up; GH replacement therapy seems to have better short term effects than on the final adult stature (Kalberg et al.2004; Kalberg et al.2007). |
| Prognosis | The most life threatening complication is represented by cardiac involvement; life expectancy also depends strictly on precocious diagnosis of respiratory and feeding complications and malignancies (Balg et al.1995; Lapunzina et al.1995; Karlberg et al. 2006). |
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