Mandibuloacral dysplasia type B (MADB): a cohort of eight patients from Suriname with a homozygous founder mutation in ZMPSTE24 (FACE1), clinical diagnostic criteria and management guidelines.

BACKGROUND: Mandibuloacral Dysplasia with type B lipodystrophy (MADB) is a rare premature aging disorder with an autosomal recessive inheritance pattern. MADB is characterized by brittle hair, mottled, atrophic skin, generalized lipodystrophy, insulin resistance, metabolic complications and skeletal features like stunted growth, mandibular and clavicular hypoplasia and acro-osteolysis of the distal phalanges. MADB is caused by reduced activity of the enzyme zinc metalloprotease ZMPSTE24 resulting from compound heterozygous or homozygous mutations in ZMPSTE24. METHODS: In 2012, and again in 2018, eight related patients from the remote tropical rainforest of inland Suriname were analysed for dysmorphic features. DNA analysis was performed and clinical features were documented. We also analysed all previously reported genetically confirmed MADB patients from literature (n = 12) for their clinical features. Based on the features of all cases (n = 20) we defined major criteria as those present in 85-100% of all MADB patients and minor criteria as those present in 70-84% of patients. RESULTS: All the Surinamese patients are of African descent and share the same homozygous c.1196A > G, p.(Tyr399Cys) missense variant in the ZMPSTE24 gene, confirming MADB. Major criteria were found to be: short stature, clavicular hypoplasia, delayed closure of cranial sutures, high palate, mandibular hypoplasia, dental crowding, acro-osteolysis of the distal phalanges, hypoplastic nails, brittle and/or sparse hair, mottled pigmentation, atrophic and sclerodermic skin, and calcified skin nodules. Minor criteria were (generalized or partial) lipoatrophy of the extremities, joint contractures and shortened phalanges. Based on our detailed clinical observations, and a review of previously described cases, we propose that the clinical diagnosis of MADB is highly likely if a patient exhibits ≥4 major clinical criteria OR ≥ 3 major clinical criteria and ≥ 2 minor clinical criteria. CONCLUSIONS: We report on eight related Surinamese patients with MADB due to a homozygous founder mutation in ZMPSTE24. In low-income countries laboratory facilities for molecular genetic testing are scarce or lacking. However, because diagnosing MADB is essential for guiding clinical management and for family counselling, we defined clinical diagnostic criteria and suggest management guidelines.

Placental pathology and neurological morbidity in preterm infants during the first two weeks after birth.

BACKGROUND: The placenta plays a crucial role during pregnancy and dysfunction causes long-term neurological problems. Identifying placenta-related risks for neurological problems shortly after birth may provide clues for early interventions aiming to improve neurological outcome. OBJECTIVE: To determine the association between placental pathology and neurological morbidity in preterm infants during the first two weeks after birth. STUDY DESIGN: Placentas of 52 singleton, preterm infants (GA: 25-31weeks, BW: 560-2250 grammes) were examined for histopathology. The infants' neurological condition shortly after birth was determined by assessing the quality of their general movements (GMs): normal, abnormal, or hypokinetic, on days 5, 8, and 15. A motor optimality score (MOS) was also assigned. RESULTS: Examination of the placentas revealed maternal vascular underperfusion (n=29), ascending intrauterine infection (AIUI) (n=19), villitis of unknown aetiology (n=6), chronic deciduitis (n=11), foetal thrombotic vasculopathy (FTV) (n=9), and elevated nucleated red blood cells (NRBCs) as a marker for foetal hypoxia (n=7). None of the placental lesions were significantly associated with the quality of GMs or MOS. CONCLUSIONS: This study indicated that placental lesions were not associated with infants' neurological condition as measured by the quality of their general movements during the first two weeks after birth.

Placental pathology is associated with illness severity in preterm infants in the first twenty-four hours after birth.

BACKGROUND: Placental pathology is associated with long-term neurological morbidity. Little is known about the association of placental pathology and illness severity directly after birth in preterm infants. OBJECTIVE: To determine the association between placental pathology and illness severity in preterm infants during the first 24 h after birth. STUDY DESIGN: Placentas of 40 preterm infants, born after singleton pregnancies (gestational age 25.4-31.7 weeks, birth weight 560-2250 g) were assessed for histopathology. Illness severity was measured using the Score of Neonatal Acute Physiology Perinatal Extension (SNAPPE). A high SNAPPE reflects high illness severity. RESULTS: Examination of the 40 placentas revealed: pathology consistent with maternal vascular underperfusion (MVU) (n=24), ascending intrauterine infection (AIUI) (n=17), villitis of unknown aetiology (VUE) (n=6), foetal thrombotic vasculopathy (FTV) (n=6), elevated nucleated red blood cells (NRBCs) (n=6), and chronic deciduitis (n=10). SNAPPE ranged from 1 to 53 (median 10). Infants with elevated NRBCs had a higher SNAPPE than infants without elevated NRBCs (median 30 vs. 10, p=0.014). The same was found for the presence of FTV (median 30 vs. 10, p=0.019). No relation existed between SNAPPE and the other placental pathologies. CONCLUSIONS: Elevated NRBCs and FTV were associated with higher illness severity during the first 24 h after birth in preterm infants. Ascending intrauterine infection was not associated with high illness severity.