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Table 2 Clinical Comparison Between ROHHAD & Prader-Willi Syndrome Phenotypes

From: ROHHAD and Prader-Willi syndrome (PWS): clinical and genetic comparison

Feature

Present in ROHHAD

Present in PWS

Main Features of ROHHAD

 Normal neonatal development

Yes

No

Rapid-onset obesity

Yes

Over 3–12 months.

Yes

Less steep trajectory.

Hypoventilation

Yes

Universal and severe - All ROHHAD patients eventually require, at a minimum, artificial ventilation during sleep, with as many as half requiring ventilation 24 h per day. If adequate ventilatory support is not provided, many ROHHAD patients suffer a cardiorespiratory arrest [1, 4, 5, 20,21,22,23,24,25].

Sometimes

Not universal, though at times severe, with some instances of cardiorespiratory arrest reported [33, 34].

Hypothalamic dysfunction

Yes

Yes

  Inability to maintain normal water balance

Yes

No

  Failed growth hormone stimulation test or growth hormone insufficiency

Sometimes

Only rarely manifests as slowed growth rate or short stature.

Yes

Growth hormone deficiency results in the characteristic short stature of PWS patients.

  Hyperprolactinemia

Yes

No

  Hypothyroidism

Sometimes

Sometimes

  Adrenal insufficiency

Sometimes

Sometimes

  Early or late puberty

Sometimes

Sometimes

Autonomic dysregulation

Yes

Yes

  Bradycardia

Sometimes

Typically temperature-related.

No

  Gastrointestinal dysmotility

Yes

Sometimes

  Neural crest tumors (typically benign)

Yes

40–50% of cases

No

  Ophthalmologic manifestations

Yes

Yes

  Pain perception altered (elevated threshold)

Yes

Yes

  Sweating (profuse)

Yes

No

  Thermal dysregulation (reduced core temperature)

Yes

Manifests most typically as hypothermia, despite a preference for light weight clothing regardless of ambient temperature.

Yes

PWS patients are seen to have unstable temperatures, becoming hyper- or hypothermic easily in hot or cold environments and responding poorly to fevers, with very high temperatures occurring when ill, and sometimes without explanation. PWS patients also have a higher threshold for thermal sensing.

  Vasomotor tone (ice cold hands and feet)

Yes

No

Main Features of PWS

 Decreased fetal movement

No

Yes

 Neonatal hypotonia

No

Yes

 Neonatal feeding problems

No

Yes

 Neonatal lethargy

No

Yes

 Delayed motor skills

No

Yes

 Hypogonadism

No

Yes

Early or delayed puberty, stalled puberty

Sometimes

Yes

 Intellectual disability or developmental delay preceding obesity

No

Most ROHHAD patients have normal IQ. However, there are rare cases of developmental delay and one case of mild intellectual disability [1]. It has been hypothesized however, that these issues occur only after inadequate oxygenation due to undiagnosed or improperly managed hypoventilation [8].

Yes

Children with PWS are delayed in reaching cognitive, motor, and language milestones. Older PWS patients have IQ scores ranging from the high range for intellectual disability to the low range of normal, with most PWS patients showing mild intellectual disability. In addition, most PWS patients have learning disabilities.

 Autism spectrum disorder

No

Yes

Diagnosed in up to a quarter of PWS patients.

Maladaptive behavior (impulsive, compulsive, manipulative)

Sometimes

It has been our experience that most ROHHAD patients, as long as their hypoventilation has been adequately managed, have no disordered behavior. However, there are case reports of severe behavioral issues including anxiety, depression, rage, aggressiveness, psychosis, and obsessive compulsive disorder [1, 23, 25, 35,36,37]. It has been hypothesized however, that these issues occur only after inadequate oxygenation due to undiagnosed or improperly managed hypoventilation, since these symptoms are not seen in patients who were diagnosed early and managed conservatively, and have not experienced a frank cardiopulmonary arrest [8]

Yes

There is a characteristic disordered behavioral pattern among PWS patients that includes temper tantrums, stubbornness, rigidity, compulsiveness, and controlling or manipulative behaviors. Psychosis is seen in a small number of PWS patients (5–10%).

Eye abnormalities (strabismus)

Yes

Yes

Growth hormone deficiency

Sometimes

Yes

 Short stature

No

Yes

Excessive weight gain independent of oral intake

Yes

Yes

 Hyperphagia-induced obesity

No

Initial weight gain is accompanied by only mild hyperphagia. But while a restricted diet can usually slow weight gain in ROHHAD, weight gain cannot be halted completely, and weight loss is exceedingly difficult to achieve.

Yes

Weight gain initially occurs without noticeable hyperphagia, but then even greater weight gain occurs with extreme hyperphagia later in childhood.

 Excessive daytime sleepiness

No

Yes

 Sleep abnormalities

No

Yes

Central apnea

Rarely

(hypoventilation is more characteristic)

Yes

Obstructive sleep apnea

Sometimes

Initially, but resolves with intervention.

Yes

 Reduced activity

No

Yes

 Higher threshold for thermal sensing

No

Yes

 Decreased saliva flow

No

Yes

 High vomiting threshold

No

Yes

Scoliosis

Sometimes

In ROHHAD, scoliosis is generally associated with thoracic neural crest tumors, whereas these tumors do not occur in PWS. However there is one reported case of a ROHHAD patient with scoliosis without a neural crest tumor [38].

Yes

Scoliosis is more common in PWS than in ROHHAD, and likely due to the PWS-related hypotonia.

Additional Features of PWS

 Small hands/feet

No

Sometimes

 Dysmorphic facial features

No

Sometimes

Central hypothyroidism

Sometimes

Sometimes

Central adrenal insufficiency

Sometimes

Sometimes

 Hip dysplasia

No

Sometimes

 Osteopenia and osteoporosis

No

Sometimes

 Skin picking

No

Sometimes

 Temperature instability

No

Sometimes

 Hypopigmentation

No

Sometimes

Seizures

Sometimes

In ROHHAD, seizures are typically linked to episodes of hypoxemia.

Sometimes

A subset of PWS patients suffers from a generalized seizure disorder of ranging severity (from febrile seizures to generalized epilepsy) [39].

  1. ‘Yes’ indicates that the symptom is a typical finding among patients
  2. ‘No’ indicates that the symptom is not typically seen among patients
  3. ‘Sometimes’ indicates that the symptom does recur among patients, but not so often as to be called ‘typical’
  4. Bolded rows represent apparently overlapping symptoms
  5. ROHHAD data are primarily taken from references [1, 5], and from our own clinical experience, with additional references as listed in the table
  6. PWS data are primarily taken from references [9,10,11], and from our own clinical experience, with additional references as listed in this Table