Clinical Description
To date, approximately 50 individuals have been identified with fumarate hydratase (FH) deficiency [Allegri et al 2010, Ottolenghi et al 2011, Kimonis et al 2012, Mroch et al 2012, Ezgu et al 2013, Saini & Singhi 2013, Tregoning et al 2013, Baştuğ et al 2014, Vara et al 2014, Ryder et al 2018, Grocott et al 2020]. The following description of the phenotypic features associated with this condition is based on these reports.
Table 2.
Select Features of Fumarate Hydratase Deficiency
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| Feature | % of Persons
w/Feature | Comment |
|---|
| Antenatal manifestations | 12/51 (23%) | Oligohydramnios, polyhydramnios, IUGR, maternal intrahepatic cholestasis,& preeclampsia |
| Prematurity | 15/51 (30%) | |
| DD | 44/51 (86%) 1 | Severe |
| Mild-moderate ID | 4/51 (8%) | |
| Hypotonia | 35/51 (68%) | |
| Seizures | 22/51 (43%) | |
| Cortical visual impairment | 13/51 (25%) | |
| Dysmorphic facial features | 20/51 (39%) | Frontal bossing, depressed nasal bridge, anteverted nares |
| Microcephaly | 17/51 (33%) | |
| Macrocephaly | 10/51 (20%) | |
| Abnormal brain imaging | 47/51 (92%) | Incl MRI, CT, & antenatal ultrasound findings; most notably: cerebral atrophy, white matter volume loss, polymicrogyria |
| Acute metabolic perturbations | 4/51 (8%) | Metabolic acidosis, lactic acidosis, hypoglycemia, hyperammonemia |
| Hematologic abnormalities | 11/51 (22%) | Neonatal polycythemia (9 persons); neutropenia (2 persons) |
| Dystonic posturing | 4/51 (8%) | |
| Excessive irritability | 3/51 (6%) | |
| Hepatic involvement | 5/51 (10%) | Cirrhosis, acute hepatic neonatal hepatic failure, biliary atresia |
DD = developmental delay; ID = intellectual disability; IUGR = intrauterine growth retardation
- 1.
Note: Some infants died in the neonatal period.
Fetal Manifestations
Few clinical reports comment on complications of affected pregnancies. However, polyhydramnios, oligohydramnios, intrauterine growth retardation, and premature birth (typically at 33-36 weeks' gestation) are reported in approximately one third of affected pregnancies [Coughlin et al 1998, Maradin et al 2006, Allegri et al 2010, Saini & Singhi 2013]. Enlarged cerebral ventricles and other brain abnormalities have been identified by fetal ultrasound [Chan et al 2017].
Neonatal and Early-Infantile Encephalopathy
Newborns with FH deficiency may be symptomatic immediately following delivery or may appear normal at birth and be discharged home from the nursery without recognized problems [Phillips et al 2006]. If symptoms are not apparent at birth, affected infants show severe neurologic abnormalities within age one week to one month, including poor feeding, failure to thrive, and hypotonia. These infants have poor eye contact and variable degrees of depressed consciousness including lethargy, stupor, and even coma. Head and neck control may be entirely absent. Infants gain weight slowly and may require tube feedings.
Epileptic seizures are common (40%-80%), with variable age of onset and seizure type [Kerrigan et al 2000, Allegri et al 2010]. Infantile spasms accompanied by hypsarrhythmia on EEG have been reported [Remes et al 2004, Loeffen et al 2005]. Seizures are often resistant to treatment.
Dysmorphic Facial Features
Abnormal facial features with a spectrum of specific findings have been widely reported and should be regarded as a hallmark feature of this condition (although perhaps not universal). Common features (>50% of affected individuals) include depressed nasal bridge, frontal bossing, and widely spaced eyes [Allegri et al 2010]. Less frequent features (<50%) include cleft ala nasi or anteverted nares, ear anomalies, or narrow forehead [Allegri et al 2010].
Head Size
Head size has been reported as microcephalic in 36% of all affected individuals [Allegri et al 2010]. However, in one large kindred (8 affected individuals in 1 consanguineous family), 88% (7 of 8 affected individuals) were reported to have "relative macrocephaly," since head sizes were within the normal range, but in association with brain imaging findings of cerebral atrophy and mild communicating hydrocephalus (enlarged extra-axial CSF spaces) [Kerrigan et al 2000]. That is, most children with FH deficiency appear have abnormally limited brain growth.
Brain Imaging Findings
The most common finding is a small brain, representative of cerebral underdevelopment. This may be described by the neuroradiologist as cerebral atrophy (73% of all individuals summarized by Allegri et al [2010]), or ventriculomegaly (82% of all individuals summarized by Allegri et al [2010]). Brain volume loss (or more likely lack of brain volume development) can be accompanied by a relative decrease in CSF reabsorption, leading to a normal head size with a small brain but modestly expanded CSF compartments. In the series of Kerrigan et al [2000], two such individuals were shunted for possible "hydrocephalus" leading to collapse of the CSF compartments and secondary microcephaly without clinical improvement.
Additional findings on MRI can include nonspecific white matter abnormalities, described as either delayed myelination or hypomyelination [Phillips et al 2006], deficient closure of the Sylvian opercula [Kerrigan et al 2000, Phillips et al 2006], and a hypoplastic brain stem [Kerrigan et al 2000, Phillips et al 2006, Tregoning et al 2013]. Abnormalities of the corpus callosum are also reported, including thinning [Maradin et al 2006, Phillips et al 2006] and absence [Coughlin et al 1998]. Hyperintense basal ganglia lesions in the caudate and thalamic nuclei, and elevated lactate on MRS have also been reported [Tregoning et al 2013]. Diffuse bilateral polymicrogyria of the cerebral cortex has also been reported, a universal feature in the eight affected individuals from one kindred reported by Kerrigan et al [2000] but also noted in three additional unrelated individuals [Zeng et al 2006, Ottolenghi et al 2011].
Clinical Course
The clinical outcome for individuals with FH deficiency is not favorable. Many individuals do not survive infancy, or may die of secondary complications (e.g., respiratory failure) during the first decade of life [Loeffen et al 2005]. Many children are unable to feed successfully, with failure to gain weight and increased risk for aspiration. Accordingly, feedings administered through gastrostomy tube may be required.
Over time, severely affected children (usually nonverbal and nonambulatory) develop evidence of spasticity, and consequently are at risk for contractures and orthopedic deformities including scoliosis. Extrapyramidal motor features, including athetosis and dystonic posturing, can also be observed. Epileptic seizures often become more frequent and less responsive to treatment. Seizures may occur daily in some individuals.
However, less severely affected children, who may be ambulatory and capable of engaging in special needs school programs (despite the presence of bilateral polymicrogyria), have also been reported [Ottolenghi et al 2011]. Consequently, counseling of families with children with FH deficiency should include recognition of the range of severity.
Heterozygotes
Most heterozygous parents are healthy. However, the finding of cutaneous leiomyomata without uterine fibroids in the mother of an affected child [Tomlinson et al 2002], a report of a mother with uterine myomas [Maradin et al 2006], the death of the mother of an affected child from "renal cell carcinoma" in a third family [VE Shih, unpublished], and the detection of renal carcinoma in an asymptomatic obligate heterozygous female raise the possibility of increased risk for HLRCC in the heterozygous relatives of children with FH deficiency (see Hereditary Leiomyomatosis with Renal Cell Cancer).
