Monozygotic Twins Discordant for ROHHAD Phenotype

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Monozygotic Twins Discordant for ROHHAD Phenotype

abstract

Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) falls within a group of pediat-ric disorders with both respiratory control and autonomic nervous system dysregulation. Children with ROHHAD typically present after 1.5 years of age with rapid weight gain as the initial sign. Subsequently, they develop alveolar hypoventilation, autonomic nervous system dys-regulation, and, if untreated, cardiorespiratory arrest. To our knowl-edge, this is the first report of discordant presentation of ROHHAD in monozygotic twins. Twin girls, born at term, had concordant growth and development until 8 years of age. From 8 to 12 years of age, the affected twin developed features characteristic of ROHHAD including obesity, alveolar hypoventilation, scoliosis, hypothalamic dysfunction (central diabetes insipidus, hypothyroidism, premature pubarche, and growth hormone deficiency), right paraspinal/thoracic ganglioneuro-blastoma, seizures, and autonomic dysregulation including altered pain perception, large and sluggishly reactive pupils, hypothermia, and profound bradycardia that required a cardiac pacemaker. Results of genetic testing for PHOX2B (congenital central hypoventilation syn-drome disease-defining gene) mutations were negative. With early rec-ognition and conservative management, the affected twin had excellent neurocognitive outcome that matched that of the unaffected twin. The unaffected twin demonstrated rapid weight gain later in age but not development of signs/symptoms consistent with ROHHAD. This discor-dant twin pair demonstrates key features of ROHHAD including the importance of early recognition (especially hypoventilation), complex-ity of signs/symptoms and clinical course, and importance of initiating comprehensive, multispecialty care. These cases confound the hypoth-esis of a monogenic etiology for ROHHAD and indicate alternative etiol-ogies including autoimmune or epigenetic phenomenon or a combina-tion of genetic predisposicombina-tion and acquired precipitant. Pediatrics

2011;128:e711–e715

AUTHORS:Pallavi P. Patwari, MD,a_{Casey M. Rand, BS,}a

Elizabeth M. Berry-Kravis MD, PhD,b_{Diego Ize-Ludlow,}

MD,c_{and Debra E. Weese-Mayer, MD}a

a_{Department of Pediatrics, Center for Autonomic Medicine in}

Pediatrics, Children’s Memorial Hospital, Northwestern University Feinberg School of Medicine, Chicago, Illinois;

b_{Departments of Pediatrics, Biochemistry and Neurological}

Sciences, Rush University Medical Center, Chicago, Illinois; and

c_{Department of Pediatrics, Division of Endocrinology, University}

of Illinois, Chicago, Illinois

KEY WORDS

autonomic nervous system, late-onset central hypoventilation syndrome, tumors of neural crest origin, overweight children, diabetes insipidus

ABBREVIATIONS

ROHHAD—rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation

ANS—autonomic nervous system

NPPV—noninvasive positive-pressure ventilation www.pediatrics.org/cgi/doi/10.1542/peds.2011-0155 doi:10.1542/peds.2011-0155

Accepted for publication May 10, 2011

Address correspondence to Pallavi P. Patwari, MD, Department of Pediatrics, Northwestern University Feinberg School of Medicine, Center for Autonomic Medicine in Pediatrics, Children’s Memorial Hospital, 2300 Children’s Plaza, Box 165, Chicago, IL 60614. E-mail: ppatwari@childrensmemorial.org PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Copyright © 2011 by the American Academy of Pediatrics

FINANCIAL DISCLOSURE:The authors have indicated they have no ﬁnancial relationships relevant to this article to disclose.

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rare disorder that includes abnormal-ities of the endocrine system (hypotha-lamic dysfunction), autonomic ner-vous system (ANS), and respiratory control (hypoventilation). Although ﬁrst described in 1965,1_{only 75 cases} currently appear in the literature. Early recognition and treatment, espe-cially of hypoventilation, is essential for ensuring optimal outcome.

Children with ROHHAD appear “nor-mal” until its onset between 1.5 and 10 years of age.2–4_{Often, the first sign is} hyperphagia with rapid, dramatic weight gain (20 – 40 lb over 6 –12 months). Other hypothalamic abnor-malities are detected months to years after the rapid-onset obesity, including altered thirst and abnormalities of an-tidiuretic hormone secretion, which results in hypernatremia or hypona-tremia, hyperprolactinemia, central hypothyroidism, precocious or de-layed puberty, growth hormone defi-ciency, and corticotropin insufficiency. In addition, many affected people de-velop obstructive sleep apnea early in the course, and all of them eventually develop central alveolar hypoventila-tion. Development of unrecognized hy-poventilation is the largest concern be-cause of risk for respiratory arrest. Consequently, ventilatory support is a mainstay of care for ROHHAD and can range from overnight noninvasive (mask) positive-pressure ventilation (NPPV) to continuous mechanical ven-tilation via tracheostomy. Later, other ANS dysregulation becomes apparent and includes decreased/absent pupil response to light, altered gastrointes-tinal motility (constipation), tempera-ture dysregulation (hyperthermia/ hypothermia), decreased pain per-ception, bradycardia, and altered dia-phoresis. Approximately 40% of chil-dren with ROHHAD develop tumors of

age. Other features include develop-mental/behavioral disorders and sei-zures. With the growing epidemic of childhood obesity, it is essential for pe-diatric physicians to be particularly at-tuned to those children who develop endogenous/pathologic obesity that does not fall into the category of exog-enously induced obesity.

CASE REPORTS

Monozygotic twin girls (conﬁrmed later with DNA identity proﬁle testing) were born at 38 weeks’ gestation via vaginal delivery to a 31-year-old G₂P₃ mother. The pregnancy was relatively uncomplicated and was without medi-cation or other substance use. Birth weight was 6 lb for twin A and 6.5 lb for twin B. Both girls had normal growth and development until 8 years of age.

Presentation of the Affected Twin

Twin B gained 75 lb between ages 8 and 9 years (Fig 1). Endocrinology evalua-tion revealed a normal androgen panel, negative workup for Cushing disease, and advanced bone age (10.5 years at chronologic age 8.5 years). In addition, she developed dilated pupils, severe constipation, and precocious puberty with menarche at 9 years. At 8.5 years, an exercise regimen and cal-orie restriction effectively stabilized her weight, but cyanosis with exertion was noted.

At 9 years, she developed cough and mild respiratory distress and was given an initial diagnosis of reactive airway disease. One week later she was diagnosed with pneumonia. Be-cause of continued complaints of cough, fatigue, shortness of breath, and perioral cyanosis without wheez-ing or nighttime cough, she was taken to the emergency department. Find-ings of severe respiratory acidosis (pH

ygen led to intubation. She failed 3 spontaneous breathing trials despite requiring “low ventilatory support.” Successful extubation was achieved with immediate initiation of NPPV for hypercarbia. Fluoroscopy indicated decreased diaphragmatic excursion but no paralysis. Further workup re-vealed lobar pneumonia, mild pulmo-nary hypertension on echocardio-gram, polycythemia (hematocrit: 61.8), elevated bicarbonate level (37 mEq/L), hypernatremia (158 mmol/L), hyper-prolactinemia (56 ng/mL), thoracic spinal dextroscoliosis with lumbar spi-nal levoscoliosis, and a BMI of 37.3 (z

score: 2.85). Chest computed tomogra-phy and MRI demonstrated a 2.5- ⫻ 3.5-cm right paraspinal (T6 –T9) mass with extension into the spinal foramen along the sympathetic chain, which was later resected and conﬁrmed to be a ganglioneuroblastoma.

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was continued but again with in-creased pressure settings to provide full ventilation along with supplemen-tal oxygen; also, an additional 1 to 2 hours of NPPV support while awake was recommended. Formal neurocog-nitive testing indicated performance in the top 10th percentile for age. At 9.9 years, medications included desmo-pressin, theophylline, levothyroxine, and docusate.

At 10.3 years, elective scoliosis re-pair was performed without compli-cation. Four months later, frequent low heart rate alarms were

docu-mented overnight with home trans-thoracic impedance monitoring (⬍50 beats per minute) without as-sociated changes in oxygenation, ap-pearance, or respiratory pattern. She did not have daytime bradycar-dia or syncope. Subsequently, a 72-hour Holter recording revealed daily low heart rates during sleep reach-ing 30 –39 beats per minute (longest r-r interval: 2.4 seconds). Parents re-ported her to be “ice cold” to touch during these nights (oral tempera-ture: 90 –91.4°F). With concern for progression and sudden death, a

cardiac pacemaker was advised. One month later, ﬁrst-degree atrio-ventricular heart block and then se-vere bradycardia (nadir: 26 beats per minute) and hypothermia (nadir: 87°F) developed, which necessi-tated hospitalization and cardiac pacemaker implantation despite a relatively stable appearance. Soon thereafter, temporal lobe seizures developed and were treated with carbamazepine.

Evaluation at a referral center for pos-sible paraneoplastic syndrome led to a diagnosis of limbic encephalitis with hypothalamic syndrome affecting au-tonomic function. Cerebrospinal ﬂuid ﬂow cytometry revealed isolated ele-vated B cell levels at 3% to 4% (normal:

⬍1%). After evaluation, improved mental status was noted before ini-tiating immunosuppressive therapy (rituximab, intravenous immunoglobu-lin, and methylprednisolone).

Neurology follow-up at 11 years re-vealed an unchanged overall condition with continued abnormal electroen-cephalograms but with possible im-provement. At 11.3 years, a positron emission tomographic scan revealed relative asymmetric tryptophan me-tabolism in the basal ganglia (activity right ⬎ left) and asymmetry in the thalamus (activity left⬎right) and the medial temporal lobe (very low activity on left). The cerebral cortex appeared symmetric, and the cerebellum ap-peared normal. With her second com-prehensive respiratory physiologic evaluation, she no longer needed con-tinuous supplemental oxygen while awake but required supplemental oxy-gen with any exertion and continued with overnight NPPV. Because ventila-tion had not signiﬁcantly improved and midface hypoplasia had developed from mask use, tracheostomy place-ment was recommended. Later, she demonstrated decreased growth ve-locity with growth hormone deﬁciency FIGURE 1

Growth chart of twins discordant for ROHHAD.

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With her third comprehensive respira-tory physiologic evaluation at 11.7 years, after tracheostomy placement and initiation of overnight mechanical ventilator support, she demonstrated improvement in her daytime spontane-ous ventilation without need for any ox-ygen, which suggests that optimal overnight ventilation effectively im-proved her wakeful breathing. Neurol-ogy evaluation found recovery of cere-brospinal ﬂuid B cells to normal levels, a normalized repeat electroencephalo-gram, and resolution of temperature dysregulation. Carbamazepine was weaned. Over 2 years, she remained stable with close follow-up by the car-diology, endocrinology, and pulmonol-ogy departments.

At 13.4 years, with her fourth compre-hensive respiratory physiologic and ANS evaluation, nocturnal mechanical ventilation via tracheostomy was continued, and she demonstrated stability of her respiratory and auto-nomic dysfunction.

Presentation of the Unaffected Twin

Twin A had normal growth and devel-opment until 11.7 years. She demon-strated normal respiratory and ANS control and normal cardiovascular re-sponse to activities of daily living dur-ing 2 comprehensive respiratory phys-iology and ANS evaluations at 11.7 years (BMI: 25.5;zscore: 1.73) and 13.4 years. Six months after menarche at 13.4 years, she continued to have weight gain (BMI: 32.1;z score: 2.18) and hypertriglyceridemia (261 mg/dL). In contrast to her sister, twin A demon-strated later onset and milder weight gain (50 lb over 20 months).

Twin A remained stable without signs/ symptoms consistent with ROHHAD. Spe-ciﬁcally, she did not demonstrate evi-dence of growth hormone deﬁciency. In addition, she demonstrated normal

respiratory evaluations while awake vealed an appropriate respiratory re-sponse to exercise testing and normal carbon dioxide and oxygen elimination. During the overnight evaluations, there was an absence of apnea, hypopnea, hypoxemia, and hypercarbia. In terms of ANS dysregulation, she had possible de-creased pupil response to light that was not quantitatively measured. Other-wise, she had appropriate cardiovascu-lar response to exercise, no episodes of bradycardia, appropriate perfusion to her extremities, and normal body tem-perature.

DISCUSSION

The unfolding story of twin B clearly demonstrates the multisystem involve-ment and complexity of ROHHAD, which requires coordinated and collabora-tive multisubspecialty care (Fig 2). The constellation and consistency of symp-toms and presentation of ROHHAD, combined with reported familial re-currence,3 _suggest _a _monogenic cause, but disease-associated genetic variation has not been identified thus far.2,3,5 _{Although identification of} mo-nozygotic twins discordant for ROHHAD does not preclude genetic variation as a causative factor in ROHHAD, and might involve modifier genes in the variable phenotype, it also indicates that stronger consideration must be given to alternative etiologies.

Epigenetic variation plays a vital role in development of disease in pediatric disorders of respiratory and auto-nomic function such as Prader-Willi and Rett syndromes. Variation in the epigenomes of identical twins accumu-lates quickly and throughout their life-time, which likely accounts for a great deal of discordance in phenotypes of twins. This case report highlights that possibility.

glioneuromas/ganglioneuroblastomas) with ROHHAD.6–9 _{Consideration should} be given to the variable timing of pre-sentation of tumors during the clinical course and lack of improvement after tumor resection. Although tumors are found in only 33% to 40% of subjects with ROHHAD2,5_{and have been} report-edly found 9 or 14 years after presen-tation,2,10_{it is unclear if these neural} crest tumors are present earlier and are slow-growing or spontaneously re-gress. The mixed results using immu-nosuppressive therapies8,9 _suggests cautious pursuit of this intervention and emphasizes the importance of in-cluding serum and cerebrospinal ﬂuid biomarkers, tumor pathology, and de-tailed notation of the evolving pheno-typic features in a larger cohort in fu-ture studies.

CONCLUSIONS

This case illustrates the importance of early recognition by the clinician of a child with rapid, dramatic weight gain but also the importance of anticipatory care that can be facilitated by referral to experts on ROHHAD. This anticipa-tory care includes early and repeated investigation for development of hypo-thalamic dysfunction, hypoventilation, ANS dysregulation, and tumors of neu-ral crest origin (imaging of the chest and abdomen along the sympathetic chain and adrenal glands).

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FIGURE 2

ROHHAD is a complex disorder that requires multisubspecialty involvement.

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DOI: 10.1542/peds.2011-0155 originally published online August 1, 2011;

2011;128;e711

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Monozygotic Twins Discordant for ROHHAD Phenotype

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